utah medicaid pharmacy and therapeutics committee drug ... · approved by the u.s. food and drug...

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Updated Report of Central Nervous System Stimulants for the

Treatment of Attention-Deficit/Hyperactivity Disorder

Amphetamine (Adzenys ER, Adzenys XR-ODT; Dyanavel XR; Evekeo, Evekeo ODT)

Dexmethylphenidate (Focalin, Focalin XR)

Dextroamphetamine (Dexedrine Spansule, Dexedrine, ProCentra, Zenzedi)

Dextroamphetamine-Amphetamine Mixed Salts (Adderall, Adderall XR, Mydayis)

Lisdexamfetamine (Vyvanse)

Methamphetamine (Desoxyn)

Methylphenidate (Adhansia XR, Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana, Jornay

PM, Metadate CD, Metadate ER, Methylin, QuilliChew ER, Quillivant XR, Relexxii, Ritalin,

Ritalin LA)

Report Finalized May 2019 Report Presented June 2019

Review prepared by: Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Research Assistant Professor, Clinical Pharmacist Joanne LaFleur, Pharm.D., MSPH, Associate Professor University of Utah College of Pharmacy University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2019 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

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Contents Executive Summary ......................................................................................................................... 3

Introduction .................................................................................................................................... 6

Table 1. FDA-Approved Central Nervous System Stimulant Agents for the Treatment of ADHD ....................................................................................................................................... 8

Methods ........................................................................................................................................ 13

Disease Overview .......................................................................................................................... 14

Table 2. DSM-5 Diagnostic Criteria for ADHD ....................................................................... 16

Treatment Guideline Recommendations ..................................................................................... 17

Table 3. Treatment Guidelines for Attention-Deficit/Hyperactivity Disorder ...................... 19

Pharmacology ............................................................................................................................... 22

Table 4. Pharmacokinetic Properties and Other Considerations for Central Nervous System Stimulant Agents ................................................................................................................... 24

Table 5. Special Population Considerations for Central Nervous System Stimulant Agents 29

Comparative Efficacy and Safety Evidence ................................................................................... 30

Figure 1. PRISMA Flow chart for Publication Screening ....................................................... 30

Table 6. Head-to-Head Randomized Controlled Trials Among FDA-Approved Stimulant Agents for ADHD ................................................................................................................... 33

Safety ............................................................................................................................................ 37

Table 7. Warnings and Precautions for the Central Nervous System Stimulant Agents ...... 39

Table 8. Adverse Events Reported with the Central Nervous System Stimulant Agents ..... 40

Summary ....................................................................................................................................... 44

References .................................................................................................................................... 45

Appendix A: Literature Search Strategies for Systematic Reviews and Randomized Controlled Trials .............................................................................................................................................. 51

Appendix B: Excluded References ................................................................................................ 55

Appendix C: Direct Evidence from Systematic Reviews and Randomized Controlled Trials ........ 57

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Executive Summary Introduction: There are currently 6 central nervous system (CNS) stimulant agents available in the United States (US) including amphetamine, dextroamphetamine, dexmethylphenidate, lisdexamfetamine, methamphetamine, and methylphenidate. CNS stimulant-containing products are approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit/hyperactivity disorder (ADHD). Some are additionally approved for the treatment of exogenous obesity, narcolepsy, or binge-eating disorder. All CNS stimulants are available in both long-acting (LA) and short-acting (SA) formulations, except lisdexamfetamine, only available as an LA formulation, and methamphetamine, only available as an SA formulation. SA stimulant formulations offer dosing flexibility at lower cost compared to LA formulations and are often used in younger children who cannot yet tolerate long-acting formulations. They are administered once to 3 times daily. LA formulations require less frequent administration, may reduce stigma at school, facilitate parental monitoring, increase adherence, improve driving performance in adolescents and youth adults, and are less likely to be abused or diverted because of the slower absorption and delivery to the CNS system compared to SA formulations. Some LA formulations are difficult to crush (eg, extended release capsules), which may also reduce the risk of abuse. However, these LA formulations may cause adverse events in the evening such as reduced appetite and sleep. Some SA and LA formulations may be more suitable for younger children such as capsules that can be opened and sprinkled into soft food or drink, orally disintegrating tablets, or oral solutions.

Chemically, amphetamine exists as 2 isomers (dextro-amphetamine and levo-amphetamine). Amphetamine products may contain only the dextro-amphetamine isomer or both isomers in different ratios. Methylphenidate exists as 2 isomers, d- and l-threo methylphenidate. Methylphenidate products may contain only the d-threo isomer (or dexmethylphenidate) or a racemic mixture of the 2 threo isomers.

Attention-Deficit/Hyperactivity Disorder is a common mental health disorder diagnosed in childhood and may continue into adulthood. ADHD is characterized by symptoms of inattention and/or hyperactivity-impulsivity that impact normal functioning and development. The full pathophysiology of ADHD is not well understood but may be related to inadequate production of norepinephrine and dopamine in the prefrontal cortex. Stimulant agents work by increasing the availability of these catecholamines, resulting in reduced ADHD symptoms.

Clinical guidelines for the treatment of ADHD include the 2011 American Academy of Pediatrics (AAP), the 2007 American Academy of Child and Adolescent Psychiatry (AACAP), and the 2018 National Institute for Health and Care Excellence (NICE) guideline, among others. The 2011 AAP guideline recommends, as first-line, behavioral therapy for preschool-aged children with ADHD and both medication and behavioral therapy for school-aged children and adolescents with ADHD. The stimulant medications have demonstrated efficacy in the treatment of ADHD and have stronger evidence supporting their role in ADHD than non-stimulant medications. They are recommended as first-line treatment options in patients requiring medication therapy. Methylphenidate or amphetamine formulations are the most commonly prescribed ADHD medications, especially in the absence of comorbidities. The non-stimulant agent, atomoxetine, is a useful alternative if methylphenidate or amphetamine treatment fail; however, it may be considered the drug of choice in patients with

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underlying anxiety disorder, severe tics, sleep disorder, or risk for stimulant abuse, misuse or diversion. US guidelines for the treatment of ADHD do not provide a preference for one stimulant agent over another or long-acting over short-acting preparations in school-aged children, adolescents, and adults. Patients should be evaluated individually to receive the most appropriate therapy for ADHD. For instance, the 2011 AAP guideline suggests that patients with a high risk of abuse, misuse, or diversion should receive formulations with no abuse potential, such as the non-stimulants, or stimulant formulations with less abuse or diversion potential, such as methylphenidate osmotic release oral system (OROS), methylphenidate transdermal patch, or lisdexamfetamine.

A previous Utah Medicaid Pharmacy and Therapeutics (P&T) Committee drug class review, “Central Nervous System Stimulants used in the Treatment of Attention Deficit Disorder,” was presented in May 2016. Based on limited comparative evidence, authors concluded that all stimulant agents are similarly efficacious and safe for the treatment of ADHD. The current drug class review provides updated evidence from systematic reviews (SRs) and randomized controlled trials (RCTs) of head-to-head efficacy and safety comparisons among the CNS stimulant agents for the treatment of ADHD.

Efficacy: Following a systematic literature search in Medline and Embase, 3 SRs and 3 newer RCTs with head-to-head efficacy and safety comparisons among ADHD stimulants were identified. The majority of comparative evidence evaluated in this drug class review comes from a report from the Oregon Drug Effectiveness Review Project (DERP) group, published in 2015. Comparative efficacy and safety evidence among ADHD stimulants is limited and most head-to-head comparisons were evaluated by a single RCT. The majority of these trials were of short duration (< 6 months) and included children and adolescents (6 to 17 years of age). In addition, most trials had small sample sizes and were considered only fair-quality. Comparative efficacy and safety evidence from short-term trials is very limited in adults and absent in young children (< 6 years). Comparative efficacy and safety data from long-term RCTs (≥ 6 months) is lacking for all age groups.

For school-aged children and adolescents with ADHD, moderate- to low-strength comparative evidence showed inconsistent results among ADHD medications. Most short-term trials showed no significant differences among ADHD stimulants (eg, OROS methylphenidate vs. immediate-release [IR] methylphenidate; extended-release [ER or XR] dexmethylphenidate vs. XR mixed amphetamine salts; lisdexamfetamine vs. XR mixed amphetamine salts; IR dextroamphetamine vs. IR methylphenidate; methylphenidate transdermal patch vs. OROS methylphenidate or IR methylphenidate). Other trials showed significantly greater ADHD symptom improvements with one ADHD stimulant over another (eg, lisdexamfetamine was better than OROS methylphenidate and methylphenidate LA was better than OROS methylphenidate for some efficacy assessments, but not all). In addition, some study results differed depending on the time point of efficacy assessment (eg, ER dexmethylphenidate had greater response from 0.5 to 6 hours post dose vs. OROS methylphenidate; however, OROS methylphenidate showed greater symptom improvements vs. ER dexmethylphenidate from 10 to 12 hours post-dose). One direct meta-analysis revealed that lisdexamfetamine has better efficacy in terms of ADHD symptom improvements than methylphenidate (formulation type not specified); however, the authors commented that further, well-conducted head-to-head studies are necessary.

For adults with ADHD, low-strength evidence suggested similar efficacy on ADHD symptom improvement when comparing IR and ER mixed amphetamine salts and when continuing IR methylphenidate or switching to OROS methylphenidate.

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Adverse Drug Reactions: The most common adverse events reported with the stimulants include headache, insomnia, increased blood pressure, abdominal pain, and decreased appetite. Weight loss and growth suppression are reported with the use of stimulants and discontinuing treatment usually results in resumption of normal growth. Sudden death in pediatric population is a concern; however, this adverse event is extremely rare and no convincing evidence is available regarding the association between the use of stimulants and sudden death. The stimulant agents are Schedule II controlled substances due to high potential for abuse. Potential risk of abuse should be assessed before prescribing a stimulant.

Most clinical trials evaluating the difference in adverse events among the ADHD stimulant agents were small, of fair quality, included pediatric population, and showed no significant differences for some comparisons or inconsistent results for other comparisons. Low-strength evidence from observational studies in children and adults suggested no significant differences in terms of sudden death and other cardiac events between amphetamines and methylphenidate. Comparative evidence in terms of abuse, misuse, and diversion was limited and mainly based on survey data.

Summary: ADHD therapy includes stimulant or nonstimulant medication and/or behavioral and psychosocial interventions depending on the patient’s age and comorbidities. US treatment guidelines do not specify a preference for one ADHD stimulant agent over another. Comparative evidence among ADHD stimulants is limited and of fair-quality. Evidence from short-term RCTs suggests that no ADHD stimulant formulation is clearly superior to another regarding efficacy and safety in school-age children, adolescents, or adults with ADHD. Some RCTs did not find significant differences among ADHD stimulants and others showed inconsistent results depending on the ADHD rating scales utilized, dose comparisons, or time point of efficacy assessment (morning, afternoon, or evening). Among similarly efficacious preparations there may be differences in the mode of delivery, pharmacokinetic profile (eg, duration of action), dosing, and adverse events. Short-term comparative evidence in young children (< 6 years) and long-term comparative evidence in all age groups is not available.

Clinicians should individualize ADHD treatment based on patient´s age, coexisting conditions, symptom profile, abuse or diversion potential, social stigma, compliance, cost, and family or patient preferences. All patients should receive a well-thought out treatment plan with close follow-up and appropriate titration of medication therapy to achieve maximum efficacy with minimal adverse reactions

In summary, current available comparative evidence on ADHD stimulants is insufficient to establish relevant efficacy and safety differences among these agents. Conclusions drawn in the 2016 Utah Medicaid Pharmacy and Therapeutics (P&T) Committee regarding ADHD stimulants are supported by the new evidence found in the current report. For the purpose of the Utah Medicaid Preferred Drug List (PDL), all ADHD stimulants may be considered equally safe and efficacious for the treatment of ADHD in children, adolescents, and adults. At least one long-acting and one short-acting formulation from each sub-category (ie, methylphenidate and amphetamines) may be included as preferred. In addition, at least one formulation from each sub-category that is suitable for patients with difficulties to swallow a whole tablet or capsule (eg, younger children) may be considered as preferred (eg, oral solutions, oral suspensions, orally disintegrating tablets, or capsules that can be opened and mixed with food or drink).

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Introduction Currently, there are more than 30 central nervous system (CNS) stimulant-containing products approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention-deficit/hyperactivity disorder (ADHD). Among them, most products are available as single-ingredient products containing 1 of the 6 different CNS stimulant agents (amphetamine, dexmethylphenidate, dextroamphetamine, lisdexamfetamine, methamphetamine, or methylphenidate) and some are available as a combination containing mixed salts of amphetamine and dextroamphetamine at different strengths (commonly called mixed amphetamine salts or MAS). Some of these medications are additionally approved for the treatment of narcolepsy, exogenous obesity, and binge eating disorder.1-30

Each CNS stimulant is available as an oral capsule or tablet formulation. Some of these agents are additionally available as oral solutions/suspensions (amphetamine, dextroamphetamine, and methylphenidate), orally disintegrating tablets (ODT; amphetamine and methylphenidate), chewable tablets (lisdexamfetamine and methylphenidate), and a transdermal patch formulation (methylphenidate). Each agent is formulated in both immediate-release (IR) and extended-release (ER) preparations, except methamphetamine which is only available as an IR formulation, and lisdexamfetamine which is only available as an ER formulation. Some formulations can be substituted for other formulations containing the same active ingredient on a mg per mg basis (eg, lisdexamfetamine capsules can be substituted for lisdexamfetamine chewable tablets). However, switching from one product to another containing a different active ingredient on a mg per mg basis (eg, from amphetamine ER ODT to mixed amphetamine salts ER capsules) should be avoided because of the risk of overdose due to different amphetamine-base compositions and pharmacokinetic profiles. Some formulations should be taken as a single, intact entity (ie, should not be crushed or chewed). Other formulations are capsules that can be opened and sprinkled into soft food or drink, orally disintegrating tablets, or oral solutions.1-

30 These latter formulations can be administered with greater ease, especially in younger children whom may have difficulty swallowing whole tables or capsules.31

Each CNS stimulant agent, except lisdexamfetamine, is available in generic form. However, several recently approved formulations of amphetamines and methylphenidate (eg, amphetamine ER oral suspension, amphetamine ER ODT, methylphenidate ER chewable tablet) and new strengths of methylphenidate remain available as branded products.1-30

The majority of ADHD stimulant-containing products are specifically approved in patients 6 years of age or older (eg, most methylphenidate- and amphetamine-containing products) or do not specify age limits in the labeled indication (eg, lisdexamfetamine- and dexmethylphenidate-containing products). The 4 IR dextroamphetamine-containing products are specifically approved in children 3 to 16 years. The recommended initial dose for each agent varies by age range and should be adjusted at weekly intervals until an adequate response is achieved. The lowest effective dosage should be administered. Renal and hepatic dosage adjustments are usually not required with the use of these agents, except with lisdexamphetamine and MAS that require a reduction in the starting dose and maximum recommended daily dose in patients with severe renal impairment. Administration frequency varies from once to thrice daily.1-30

A previous Utah Medicaid Pharmacy and Therapeutics (P&T) Committee drug class review, “Central Nervous System Stimulants used in the Treatment of Attention Deficit Disorder,” was presented in May

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2016. The following motions with respect to the Medicaid Preferred Drug List (PDL) were passed during the P&T meeting on May 19, 2016:

• “All drugs in this class are equally safe and effective.”

• “Include at least one formulation from both the amphetamine and methylphenidate sub-class that does not have to be taken as a single, intact entity as preferred on the PDL.”

• “Include at least one short-acting and one long-acting formulation as preferred on the PDL.”32

The current drug class review provides updated evidence from systematic reviews (SRs) and randomized controlled trials (RCTs) of head-to-head efficacy and safety comparisons among the CNS stimulants for the treatment of ADHD. In addition, relevant information from the previous P&T report on ADHD stimulants (eg, disease overview, pharmacokinetics, and safety) will be included.

Table 1 provides specific information concerning labeled indications and dosing recommendation for the CNS stimulant-containing products. Gray shaded text highlights new FDA approved products or formulations identified since the publication of the 2016 P&T report on ADHD stimulants.

On the Utah Medicaid PDL published on April 2019, the following 11 ADHD stimulant products, including immediate-release formulations (tablet and oral solution) and extended-release formulations (capsule, tablet, chewable tablet, and oral suspension), are listed as preferred:

• Ten single-ingredient stimulant products, including 6 products containing methylphenidate (Aptensio XR, Concerta, Methylin solution, generic methylphenidate IR tablet, Quillichew ER, and Quillivant suspension), 2 products containing amphetamine (Dyanavel XR and Evekeo), 1 product containing dexmethylphenidate (Focalin XR), and 1 product containing lisdexamfetamine (Vyvanse).

• One IR generic combination product containing amphetamine and dextroamphetamine

Single-ingredient products containing dextroamphetamine or methamphetamine and other formulation types of methylphenidate or amphetamines are listed as non-preferred. Brand combination products of amphetamine with dextroamphetamine are also non-preferred. Upon review of Medicaid fee-for-service and accountable care organization utilization data for 2018, the 5 most commonly utilized ADHD stimulants in the overall population (all age groups combined) were amphetamine/dextroamphetamine mixed salts (IR tablets and ER capsules), methylphenidate IR tablets, Concerta ER tablets (osmotic release), and methylphenidate ER tablets (osmotic release).

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Table 1. FDA-Approved Central Nervous System Stimulant Agents for the Treatment of ADHD1-30

Generic Name

Brand Name Preparations

(Approval date) (Availability of Generic)

Labeled Indication(s) Recommended Dosage for the Treatment of

ADHD

Amph

etam

ine

Adzenys ER ER oral suspension 1.25 mg/mL (September 2017)

Treatment of ADHD in patients ≥ 6 years old

• Children 6 to 12 years and adolescents: - Initial dose: 6.3 mg QD - Maximum dose: 18.8 mg/day for

children 6-12 years and 12.5 mg/day for adolescents ≥13 years

• Adults: 12.5 mg QD

Adzenys XR-ODT ER ODT 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg (January 2016) Dyanavel XR ER oral suspension 2.5 mg/mL (October 2015)

Children ≥ 6 years: 2.5 mg or 5 mg QD; maximum daily dose: 20 mg

Amph

etam

ine

sulfa

te Evekeo

Oral tablet 5 mg and 10 mg (August 2012) (Generic available)

Treatment of ADHD (not recommended in children < 3 years) * Other labeled indications: narcolepsy and exogenous obesity

• Pediatric patient 3 to 5 years: 2.5 mg/day

• Pediatric patient ≥6 years: 5 mg QD or BID

Evekeo ODT ODT 5 mg, 10 mg, 15 mg, 20 mg (January 2019)

Treatment of ADHD in pediatric patients 6 to 17 years of age

• Recommended starting dose: 5 mg QD or BID; increase the dose until an optimal response is achieved

Dexm

ethy

lphe

nida

te h

ydro

chlo

ride

Focalin Oral tablet 2.5 mg, 5 mg, 10 mg (November 2001) (Generic available)

Treatment of ADHD (efficacy established in pediatric patients 6-17 years)

• Patients new to methylphenidate: 2.5 mg BID

• Patients currently on methylphenidate: use half the total daily dose of racemic methylphenidate

• Maximum dose: 20 mg/day)

Focalin XR ER oral capsule 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 40 mg (May 2005) (Generic available)

Treatment of ADHD (efficacy established in pediatric patients 6-17 years and adults)

• Patients new to methylphenidate: Pediatric patients: 5 mg QD Adult patients: 10 mg QD

• Patients currently on methylphenidate: use half the total daily dose of racemic methylphenidate

• Dosage may be increased in 5 to 10 mg weekly in pediatric patients and adults, respectively (maximum dose: 30 mg/day in pediatrics and 40 mg in adults)

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Generic Name




ADHD

Dext

roam

phet

amin

e su

lfate

Dexedrine Spansule SR oral capsule 5 mg, 10 mg, and 15 mg (August 1976) (Generic available)

Treatment of ADHD in patients 6 to 16 years (not recommended in children < 6 years) * Other labeled indications: narcolepsy

Pediatric patient ≥6 years: 5 mg QD or BID; increase the dose until an adequate response is achieved

Dexedrine Oral tablet 5 mg, 10 mg (February 1976) (Brand DSC; generic available) Oral solution 5 mg/5 mL (February 1976, DSC) (Brand DSC; generic available only)

Treatment of ADHD in children 3 to 16 years * Other labeled indications: narcolepsy

• Pediatric patient 3 to 5 years: 2.5 mg/day; increase the dose until an adequate response is achieved

• Pediatric patient ≥ 6 years: 5 mg QD or BID; increase the dose until an adequate response is achieved

ProCentra Oral solution 5 mg/5 mL Zenzedi Oral tablet 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 30 mg

Dext

roam

phet

amin

e/

Amph

etam

ine

mix

ed sa

lts

Adderall 5, 7.5, 10, 12.5, 15, 20, 30 Oral tablet 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg (January 1960) (Brand DSC; generic available) * Contains amphetamine aspartate; amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate

Treatment of ADHD (Not recommended for children < 3 years) * Other labeled indications: narcolepsy

• Pediatric patients 3-5 years: 2.5 mg/day; increase the dose until an adequate response is achieved

• Pediatric patient ≥6 years: 5 mg QD or BID; increase the dose until an adequate response is achieved

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Generic Name




ADHD

Dext

roam

phet

amin

e/

Amph

etam

ine

mix

ed sa

lts (c

ontin

ued)

Adderall XR 5, 10, 15, 20, 25, and 30 ER oral capsule 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg (October 2001) (Generic available) * Contains amphetamine aspartate; amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate

Treatment of ADHD (efficacy established in pediatric patients 6-17 years and adults)

• Pediatric patients (6-17 years): 10 mg QD

• Adults: 20 mg QD * Dosage should be adjusted with severe renal impairment

Mydayis ER oral capsule 12.5 mg, 25 mg, 37.5 mg, 50 mg (June 2017) * Contains amphetamine aspartate; amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (different strengths compared to Adderall XR)

Treatment of ADHD in patients ≥ 13 years

• Pediatric patients (13-17 years): Initial dose (12.5 mg); daily dose may be increased 12.5 mg weekly (maximum dose: 25 mg)

• Adults: Initial dose (12.5 mg); daily dose may be increased 12.5 mg weekly (maximum dose: 50 mg)

* Dosage should be adjusted with severe renal impairment. Use in patients with ESRD is not recommended

Lisd

exam

feta

min

e Di

mes

ylat

e

Vyvanse Oral capsule: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg (February 2007) Oral chewable tablet: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (January 2017)

Treatment of ADHD * Other labeled indications: moderate to severe binge eating disorder (BED) in adults

Adult and pediatric patients: • Initial dose: 30 mg QD; daily dose may

be increased 10 mg to 20 mg weekly • Recommended dose: 30 mg to 70 mg

daily (maximum dose: 70 mg/day) * Dosage should be adjusted with severe renal impairment and ESRD

Met

ham

phet

amin

e

Desoxyn Oral tablet 5 mg (December 1943) (Generic available)

Treatment of ADHD in children > 6 years * Other labeled indications: exogenous obesity

• Recommended dosage: 5 mg QD or BID; daily dose may be increased in 5 mg at weekly intervals until an adequate response is achieved

• Usual effective dose: 20-25 mg/day

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Generic Name




ADHD

Met

hylp

heni

date

Adhansia XR ER oral capsule 25 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg (February 2019)

Treatment of ADHD in patients ≥ 6 years

Recommended dose: 25 mg QD to 70 mg/daily (in pediatric patients) or 85 mg/daily (in adults)

Aptensio XR ER oral capsule 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (April 2015)


Pediatric patients ≥ 6 years: 10 mg QD; dosage may be increased weekly in 10 mg increments (maximum dose: 60 mg/day)

Concerta ER oral tablet 18 mg, 27 mg, 36 mg, 54 mg (August 2000) (Generic available)

Treatment of ADHD in children ≥ 6 years, adolescents, and adults ≤ 65 years

• Patients new to methylphenidate: Pediatric patients: - Children and adolescents: 18 mg QD - Adult patients: 18 to 36 mg QD

• Dosage may be increased weekly in 18 mg increments (maximum dose: 54 mg/day for children and 72 mg/day for adults)

• Patients currently on methylphenidate: Dosing based on current regimen and clinical judgment

Cotempla XR-ODT ER ODT 8.6 mg, 17.3 mg, 25.9 mg (June 2017)

Treatment of ADHD in pediatric patients 6-17 years

Children 6-17 years: 17.3 mg QD; dosage may be increased weekly in 8.6 mg to 17.3 mg increments per day (maximum dose: 51.8 mg)

Daytrana ER transdermal patch 10 mg/9 hr, 15 mg/9 hr, 20 mg/9 hr, 30 mg/9 hr (April 2006)


Apply Daytrana to the hip area Initial dose: 10 mg QD; dose may be titrated at weekly intervals

Jornay PM ER oral capsule 20 mg, 40 mg, 60 mg, 80 mg, 100 mg (August 2018)

Treatment of ADHD in children ≥ 6 years

Initial dose: 20 mg daily in the evening; dosage may be increased weekly in 20 mg increments (maximum daily dose: 100 mg)

Metadate CD ER oral capsule 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (April 2001) (Generic available)

Treatment of ADHD (efficacy established in children 6 to 15 years)

Initial dose: 20 mg QD; may be adjusted weekly in 10 to 20 mg increments; (maximum dose: 60 mg/day)

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Generic Name




ADHD

Met

hylp

heni

date

(con

tinue

d)

Metadate ER ER oral tablet 10 mg and 20 mg (June 1988) (ER tablet 10 mg DSC; generic available for ER tablet 10 mg and 20 mg)

Treatment of ADHD * Other labeled indications: narcolepsy

10 mg to 60 mg/day (administered in 2 or 3 divided doses)

Methylin Oral solution 5 mg/5 mL, 10 mg/5 mL (December 2002) (Generic available) Chewable tablet 2.5 mg, 5 mg, 10 mg (April, 2003) (Brand DSC, generic available)

Treatment of ADHD (Not recommended for children < 6 years)

• Adults: Average dose: 20 to 30 mg • Pediatric patients ≥ 6 years: initial dose

5 mg BID; may be adjusted weekly in 5 to 10 mg increments (maximum dose: 60 mg/day)

Quillichew ER ER oral chewable tablet 20 mg, 30 mg, 40 mg (December 2015)


Children ≥ 6 years: Initial dose: 20 mg QD; may be adjusted by 10, 15, or 20 mg at weekly intervals (maximum dose: 60 mg/day)

Quillivant XR ER oral suspension 25 mg/5 mL (September 2012)


Initial dose: 20 mg QD; may be adjusted in 10 to 20 mg increments at weekly intervals (maximum dose: 60 mg/day)

Relexxii ER oral tablet 72 mg (December 1955) (Generic available)

Treatment of ADHD in children ≥ 6 years, adolescents, and adults ≤ 65 years

• 18 mg to 72 mg QD

Ritalin Oral tablet 5 mg, 10 mg, 20 mg (December 1955) (Generic available) Ritalin-SR ER tablet 20 mg (Brand DSC; generic available)

Treatment of ADHD in pediatric patients ≥ 6 years and adults * Other labeled indications: narcolepsy

• Adults: Average daily dosage is 20 to 30 mg (in 2 or 3 divided doses). Maximum daily dose: 60 mg/day

• Pediatric patients ≥ 6 years: 5 mg BID; may be adjusted in 5 to 10 mg increments at weekly intervals (maximum daily dose: 60 mg/day)

Ritalin LA ER oral capsule 10 mg, 20 mg, 30 mg, 40 mg, 60 mg (June 2002) (Brand DSC; generic available)

Treatment of ADHD in pediatric patients 6 to 12 years

Initial dose: 20 mg QD (10 mg QD for some patients); may be adjusted in 10 mg increments at weekly intervals (maximum daily dose: 60 mg/day)

Note: Gray shaded text highlights new FDA approved products or formulations identified since the publication of the 2016 Pharmacy & Therapeutics report on ADHD stimulants Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BID, twice daily; DSC, discontinued; ER, extended release; FDA, Food and Drug Administration; ODT, orally disintegrating tablet; QD, once daily; XR, extended release

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Methods

Literature Search

Search strategies were developed for systematic reviews (SRs) and randomized controlled trials (RCTs) in OVID Medline and Embase. Strategies consisted of controlled vocabulary, such as Medical Subject Headings (MeSH), and keyword phrases. Two methodological filters were used, one for SRs and meta-analyses (MAs) and another for RCTs. Results were limited to English language. Based on the search strategy described in the previous P&T report on ADHD, databases were searched from 2015 through April 18, 2019 for SRs and MAs. Based on the literature searches described in the SRs/MAs identified, the RCT search was narrowed from 2017 to April 18, 2019. In Embase, we excluded conference abstracts. Furthermore, a literature search for systematic reviews was performed in Epistemonikos database from 2015 to April 24, 2019. The complete search strategies and terms are available in Appendix A. Authors conducted a grey literature search including the websites for the Oregon Drug Effectiveness Review Project (DERP) group, the Canadian Agency for Drugs and Technologies in Health (CADTH), and the Agency for Healthcare Research and Quality (AHRQ).

Authors also screened the reference lists of related SRs and the following relevant websites for further information:

1. For guidelines addressing ADHD management: websites of the American Academy of Psychiatry (AAP), the American Academy of Child & Adolescent Psychiatry (AACAP), the Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA), and the National Institute for Health and Care Excellence (NICE)

2. For FDA-approved prescribing information (package inserts): the US FDA website (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/) and DailyMed website (an official provider of US FDA drug-label information)

3. Evidence-based drug information databases: Micromedex and Lexicomp

Screening

Two review authors screened titles and abstracts. Conflicts were resolved via discussion between reviewers. The full texts for all citations receiving 2 inclusion votes were retrieved; inclusion was determined by the lead author. Figure 1 on page 30 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart33 for the review process.

Inclusion and Exclusion Criteria

SRs and/or MAs (hereinafter referred to as SRs) of RCTs and RCTs providing head-to-head efficacy or safety comparisons among the ADHD stimulants listed in Table 1 were included. For product comparisons where an SR provided robust data, we examined only those trials or SRs published after the search date of the robust SR. Network meta-analyses including standard pairwise meta-analyses of a stimulant agent vs. another were included. The primary efficacy endpoint of included studies should measure ADHD symptom improvements, as rated by teachers, physicians, or clinical investigators using ADHD rating scales.

14

Excluded references met the following criteria:

• SRs including observational studies, registries, and retrospective studies in the pooled analyses

• Reviews not using systematic review methodology

• Network meta-analyses including indirect comparisons only

• SRs or RCTs comparing stimulants versus non-stimulants or placebo

• Single studies such as observational studies, pharmacodynamic studies, cost-effectiveness analyses. studies evaluating non-FDA approved doses, registries, or pilot studies

A list containing the excluded references from the full-text screening is provided in Appendix B.

Disease Overview

Mental illness includes mental disorders characterized by abnormalities in behavior, mood, thinking, or feeling.34 These disorders may be episodic, of short duration or chronic, and may impair social abilities and daily functioning in school, work, and home settings.34 More than 200 types of mental illnesses may be diagnosed including various forms of anxiety disorders, ADHD, disruptive behavioral disorders, depression and other mood disorders, eating disorders, personality disorders, posttraumatic stress disorder, schizophrenia spectrum and other psychotic disorders, and substance use disorders.34 In 2017, a national survey on drug use and health reported that approximately 19% of all Americans 18 years and older had a mental illness in the previous year.35 In this survey, the most commonly reported mental illnesses in American adults were anxiety and mood disorders (eg, major depression).36 A national survey (2001-2004) of American adolescents between 13 and 18 years showed that 49.5% had a mental illness diagnosed during their lifetime.37 In addition, this survey indicated that the most commonly reported mental illnesses in American adolescents were anxiety, followed by behavior disorders (including ADHD), mood disorders, and substance use disorder.37

Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inattention and/or hyperactivity-impulsivity.38,39 ADHD is most often diagnosed during childhood and may continue into adulthood.39 The disorder was first named as hyperkinetic reaction in childhood in 1968 by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 2nd edition (DSM-II). The term evolved to Attention Deficit Disorder (ADD) in 1980 (DSM-III) and finally to ADHD in 1987 (DSM-III-revised).40

According to parent-report data from the third National Survey of Children’s Health (NSCH) conducted in 2011-2012, the estimated percentage of school-aged children (4 to 17 years old) ever diagnosed with ADHD was 11% (6.4 million) in the United States (US) and 8.3% in Utah.39,41,42 The US prevalence of ADHD rose by 42% between 2003 and 2011.39,42 A redesigned 2016 NSCH showed an estimated prevalence in the US of 9.4% (6.1 million) among children 2 to 17 years old based on parent report.43-45 In general, ADHD is diagnosed more frequently in school-aged boys (1 in 5) than girls (1 in 11) and the average age of first onset of the disease is 7 years.39 In US adults, the prevalence of ADHD is estimated

15

to be 4.4% according to a National Comorbidity Survey Replication (NCS-R) conducted between 2001 and 2003.46-48 The economic burden of childhood ADHD in the US health care system reaches more than $38 billion per year, including costs associated with the treatment of patients, healthcare of family members, education, juvenile justice, and lost productivity for family members.49,50 About 64% of children with ADHD have another mental, emotional, or behavioral disorder, including behavior or conduct problem (52%), anxiety (33%), depression (17%), autism spectrum disorder (14%), and Tourette syndrome (1%).43,44 This may further contribute to increased health-care costs and morbidity. Increasing mental health disorder education and screening for other disorders can help to improve patient outcomes and reduce overall costs.51

Etiology and Risk Factors

ADHD causes and risk factors are unknown.52 Evidence suggests that genetics, brains injury, exposure to environmental agents (eg, lead) in pregnancy or young age, alcohol and/or tobacco use in pregnancy, a premature birth, and low birth weight are associated with the development of ADHD.52

Diagnosis

Attention-deficit/hyperactivity disorder is defined by Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) as a neurodevelopmental disorder characterized by “impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity,” which produce difficulty functioning in social, academic, and occupational settings.53 Inattention and disorganization involve difficulty sustaining focus on tasks and organizing activities. Hyperactivity-impulsivity involves restlessness, fidgeting, excessive movement/talking, and hasty actions that interfere with other people’s tasks.53 These symptoms are typically not consistent with the behavior considered normal for that age and developmental stage.53 ADHD may be divided into 3 different types based on symptoms: predominantly inattentive, predominantly hyperactive-impulsive, or combined presentation with symptoms of both types equally exhibited.38,53 There is not a specific test to diagnose ADHD and other mental disorders may have symptoms consistent with ADHD.52 According to DSM-5 diagnostic criteria for ADHD, diagnosis requires 6 or more symptoms of inattention and/or hyperactivity-impulsivity for children (≤ 16 years old) or 5 or more symptoms for adolescents and adults (≥ 17 years old) that have persisted for at least 6 months and are inconsistent with the stage of development.38,53 In addition, further requirements are necessary to confirm the diagnosis of ADHD.38,53 Table 2 includes DSM-5 diagnostic criteria for ADHD and examples of ADHD symptoms. The 2011 American Academy of Pediatrics (AAP) guideline concerning diagnosis and treatment of ADHD in children and adolescents recommends meeting all DSM-5 criteria for the diagnosis of ADHD.51

16

Table 2. DSM-5 Diagnostic Criteria for ADHD53 Age Range DSM-5 Diagnostic Criteria Symptoms Children (≤ 16 years old)

1. Six or more symptoms of inattention and/or hyperactivity-impulsivity that have persisted for at least 6 months and are inconsistent with the stage of development

2. Symptoms are present before age 12 in 2 or more settings (eg, at home and school)

3. Symptoms reduce the quality of school/work and social functioning

4. Symptoms do not adequately define other mental disorders

Examples of symptoms of inattention: • Failure to pay close attention to details • Make careless mistakes • Trouble maintaining attention on a single task • Inability to listen • Failure to finish duties at school, home, or

work • Trouble organizing tasks • Avoids tasks that require mental effort over a

long period of time • Loses things (eg, school material) • Easily distracted or forgetful Examples of symptoms of hyperactivity-impulsivity: • Fidgets • Trouble remaining seated • Feels restless (may run or climb in

inappropriate circumstances) • Trouble participating in quiet activities • "On the go” • Talks excessively and speaks out of turn • Trouble waiting turn • Often interrupts or intrudes

Adolescents and adults (≥ 17 years old)

1. Five or more symptoms of inattention and/or hyperactivity-impulsivity that have persisted for at least 6 months and are inconsistent with the stage of development

2. Symptoms are present before age 12 in 2 or more settings (eg, at home and school)

3. Symptoms reduce the quality of school/work and social functioning

4. Symptoms do not adequately define other mental disorders

Abbreviations: DSM-5, Diagnostic and Statistical Manual of Mental Disorders (5th edition)

Common behavior rating scales are used for the initial screening for ADHD and evaluation of treatment response. These include ADHD rating scale-IV (ADHD-RS-IV), Academic Performance Rating Scale (APRS), Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP), or Conners Rating Scales, among others.54

Treatment Strategies

Treatment objectives are to reduce ADHD symptoms, increase functional performance, and eliminate behavioral problems. Treatment strategies for ADHD depend on the patient’s age and may include behavior therapy alone or behavior therapy with medication therapy.51 Behavioral therapies include teaching the child new behaviors to replace those causing disruptions to activities of daily living as well as teaching the child’s parents new skills and enforcing their current skills to help the child manage negative behaviors.55 Stimulant and nonstimulant agents are considered the mainstay of ADHD pharmacological treatment. Stimulants, including amphetamine and methylphenidate preparations, are the most widely used ADHD treatments, are fast-acting, and are more efficacious than non-stimulants in reducing ADHD symptoms.51,55-57 Non-stimulant agents, including atomoxetine, guanfacine, and clonidine, are not as fast-acting as stimulants but are long-acting (up to 24 hours) and may be associated with fewer adverse effects.55,56,58,59 Stimulants may be used in combination with nonstimulants (eg, a stimulant with either clonidine or guanfacine) if patients do not respond to stimulants alone.60 Some

17

evidence suggests antidepressants alone or in addition to a stimulant agent may be used, off label, in children with ADHD.54,58,61

FDA-approved medications for the treatment of ADHD are available as short-acting (SA) or long-acting (LA) preparations. SA stimulant formulations are administered more frequently than LA formulations. They offer some advantages compared to LA formulations such as dosing flexibility and lower cost.62 SA preparations comprise initial treatment for many children to flexibly adjust to the optimal dose. They are especially useful in children less than 16 kg who require doses lower than those available with LA products.54,62 LA formulations require less frequent administration, are more likely to reduce stigma of school-age children because they do not need to take medicines at school, facilitate parental monitoring, increase adherence, improve driving performance in adolescents and youth adults, and are less likely to be abused or diverted because of the slower absorption and delivery to the CNS system compared to SA formulations.54,56,62,63 Some of the LA formulations are difficult to crush (eg, extended release capsules), which may avoid intranasal or intravenous administration.63 However, LA formulations may cause adverse events in the evening such as reduced appetite and sleep.62

Multiple trials of different medications at various doses are often required to find the optimal drug therapy in children with ADHD.55 Effective treatment plans should include behavioral and/or medication therapy, close monitoring by doctors and parents, and frequent follow-ups to find the medications and doses that most benefit the patient.51,55,58

In 2016, NSCH data of parent-reported ADHD medication and behavior therapy use showed that 62% of children 2 to 17 years old with ADHD received medication for ADHD and 47% received ADHD behavior therapy in the previous year.44,45 Among children 2 to 5 years old with ADHD, 60% received behavior therapy.44 In Utah, a national parental-report survey conducted between 2009 and 2010 in children 4 to 17 years old with special health care needs indicated that 66% received medication for ADHD in the past week, 42% received behavior treatment in the previous 12 months, and 30% received both treatments.64 This survey showed similar numbers nationally (74%, 44%, and 31% for medication use, behavior therapy use, and both treatments, respectively).64

Treatment Guideline Recommendations Clinical guidelines for the treatment of ADHD include the 2011 American Academy of Pediatrics (AAP),51 the 2007 American Academy of Child and Adolescent Psychiatry (AACAP),54 and the 2018 National Institute for Health and Care Excellence (NICE) guideline,65 among others. Table 3 includes a summary of the most current guideline recommendations.

Overall, guidelines include the following treatment recommendations depending on patient´s age. Note that treatment recommendations may differ between countries due to differences in the national drug approval process, incorporation of cost-effectiveness analyses, and expert opinion considerations.66

1. In preschool-aged children with ADHD (4 to 5 years old according to the AAP guideline or children under 5 years old according to the NICE guideline), behavioral therapy alone (especially parent training) is recommended as first-line treatment before offering medication due to limited evidence on efficacy and lack of evidence on long-term safety of medications in this

18

population.51,65 If behavior therapy does not provide significant improvements and symptoms causing significant impairments persist, both guidelines suggest further specialist advice before offering medication for ADHD.51,65 Although limited information on ADHD medications is available in this age group, the 2011 AAP guideline considers that methylphenidate may be used if behavior therapy fails.51

2. In children with ADHD (6 to 11 years old), treatment with both FDA-approved medication and behavioral therapy is preferred according to the AAP guideline.51 The 2011 AAP and 2007 AACAP guidelines state that stimulants are supported by stronger evidence compared to non-stimulants. Authors do not give a preference for one stimulant agent over another.51,54 The 2007 AACAP practice parameter considers immediate- and extended-release formulations equally efficacious; however, authors state that one formulation may be more convenient than others in specific circumstances.54 In contrast, the 2018 NICE guideline suggests methylphenidate (either short- or long-acting) as first-line treatment and amphetamine agents as second-line treatments (lisdexamfetamine first, then dexamphetamine).65

3. In adolescents (12 to 18 years old), treatment with both FDA-approved medication and behavioral therapy is preferred according to the AAP guideline.51 The 2011 AAP and 2007 AACAP guidelines do not give a preference for one ADHD stimulant agent over another. The 2018 NICE guideline includes the same treatment preference for children and adolescents with ADHD.51,54 The potential for diversion or abuse should be evaluated and administration of agents with no abuse potential (eg, non-stimulants) or stimulants with less risk of abuse (eg, lisdexamfetamine, methylphenidate transdermal patch, or OROS methylphenidate) may be considered, as stated in the 2011 AAP guideline.51

4. In adults with ADHD, the 2018 NICE guideline suggests lisdexamfetamine or methylphenidate as first-line treatment. Dexamphetamine may be considered if patients do not tolerate lisdexamfetamine. Authors of this guideline consider prescribing an ADHD-focused psychological intervention if there are medication concerns (eg, non-adherence or ineffectiveness) or if symptoms still cause significant impairments with medication.65

In summary, ADHD medication in children, adolescents, and adults usually includes a stimulant agent (either methylphenidate or amphetamine) as first-line.51,56,62,65 The non-stimulant, atomoxetine, is usually suggested as third-line if methylphenidate or amphetamine treatment fail; however, it may also be the drug of choice in patients with underlying anxiety disorder, severe tics, sleep disorder, or risk for abuse, misuse, or diversion of stimulant agents.51,61,67 Most guidelines do not provide a preference between short- and long-acting preparations.51,56,62,65

Choice of ADHD medication therapy should be individualized and depends on patient’s age, coexisting conditions, symptom profile, duration of drug effect, abuse or diversion potential, social stigma, convenience, compliance, cost, and family or patient preferences.51,56,62,63 All patients should receive a well-thought out treatment plan with close follow-up and appropriate titration of medication therapy to achieve maximum efficacy and minimum adverse reactions.51,58,63

19

Table 3. Treatment Guidelines for Attention-Deficit/Hyperactivity Disorder Organization/Guideline Recommendations

American Academy of Pediatrics

ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/ Hyperactivity Disorder in Children and Adolescents; 201151

Preschool-aged children (4–5 years of age) • Evidence-based parent- and/or teacher-administered behavior therapy as the first

line of treatment • Methylphenidate if the behavior interventions do not provide significant

improvement and there is moderate-to-severe continuing disturbance in functioning

Elementary school–aged children (6–11 years of age) • FDA–approved medications for ADHD and/or evidence-based parent and/or

teacher-administered behavior therapy, preferably both o Evidence is strong for stimulant medications and sufficient but less strong for

atomoxetine, extended-release guanfacine, and extended-release clonidine (in that order)

Adolescents (12–18 years of age) • FDA–approved medications for ADHDs should be prescribed and evidence-based

parent and/or teacher-administered behavior therapy may be prescribed, preferably both

Medication therapy in all patient age groups should be titrated to achieve maximum benefit with minimum adverse effects

National Institute for Health and Care Excellence (NICE)

Attention deficit hyperactivity disorder: diagnosis and management (NG87; March 2018)65

General recommendations: • Drug treatment should only be initiated by an ADHD specialist Children < 5 years • An ADHD-focused group parent-training program to parents or caregivers of

children < 5 years with ADHD should be offered as first-line treatment • If ADHD symptoms still cause a significant impairment in the child, “do not offer

medication for ADHD for any child < 5 years without a second specialist opinion from an ADHD service with expertise in managing ADHD in young children (ideally a tertiary service)”

Children ≥ 5 years and young people with ADHD: • Offer ADHD-focused parent-training program to parents or carers • Offer medication therapy if ADHD symptoms still cause a significant impairment in

at least 1 domain after implementing and reviewing environmental modifications • First line treatment: methylphenidate (either short or long acting)

o Consider switching to lisdexamfetamine if patients had inadequate response in terms of ADHD symptoms and associated impairment to a 6-week trial of methylphenidate

o Consider dexamfetamine if patients cannot tolerate the longer effect profile of lisdexamfetamine

• Offer atomoxetine or guanfacine if: o Patients cannot tolerate methylphenidate or lisdexamfetamine OR

symptoms “have not responded to separate 6-week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses”

• Consider a course of CBT for young people “who have benefited from medication but whose symptoms are still causing a significant impairment in at least one domain”

Adults with ADHD: • Offer medication therapy if ADHD symptoms still cause a significant impairment in

at least 1 domain after implementing and reviewing environmental modifications

20


• First line treatment: lisdexamfetamine OR methylphenidate • Consider dexamfetamine if patients cannot tolerate the longer effect profile of

lisdexamfetamine • Offer atomoxetine if patients cannot tolerate or have not responded to

methylphenidate or lisdexamfetamine • Non-pharmacological treatment such as an ADHD-focused psychological

intervention should be considered if there are issues with medication (eg, non-adherence and ineffectiveness) or if symptoms still cause significant impairments with medication

Other medication choices: • If ADHD symptoms do not respond to ≥ 1 stimulants and 1 non-stimulant, a

second opinion or reference to a tertiary ADHD service is required • Avoid the use of the following medications without advice from a tertiary ADHD

service: o “Guanfacine for adults o Clonidine for children with ADHD and sleep disturbance, rages or tics o Atypical antipsychotics in addition to stimulants for people with ADHD

and coexisting pervasive aggression, rages or irritability” o Other medications non included in the above recommendations

British Association for Psychopharmacology Evidence based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology; 201456

Children and adolescents: • Children with severe ADHD: offer pharmacological treatment • Children with moderate ADHD: consider pharmacological treatment if no response

to psychological interventions • Treatment of choice: psychostimulant medication • Atomoxetine may be used if “there is a risk of misuse of psychostimulants by

children or the adults supporting the child” • “Appropriate child and family-based psychological interventions should be

available to all children with ADHD” • Patient and parental preferences should be considered Adults: • First-line therapy: stimulants. Atomoxetine is first-line in patients with substance

use disorders Canadian ADHD Resource Alliance (CADDRA) Canadian ADHD Practice Guidelines (CAP-Guidelines); 201159

Children, adolescents, and adults: • First-line agents: long-acting preparations (eg, amphetamine mixed salts,

methylphenidate, lisdexamfetamine) • Second-line/Adjunctive agents: short- and intermediate- acting preparations (eg,

dextroamphetamine and methylphenidate), atomoxetine, and guanfacine XR (children 6-12 years)

Canadian Agency for Drugs and Technologies in Health (CADTH) Guidelines and Recommendations for ADHD in Children and Adolescents; 201162

• First-line therapy: stimulants (methylphenidate or amphetamine). Consider symptom profile when choosing short- or long- acting preparations

• Third-line therapy: atomoxetine. In the presence of comorbidities, atomoxetine may be considered before stimulant agent

21


American Academy of Child and Adolescent Psychiatry (AACAP)

Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder; 200754

Initial medication therapy should be with a trial of an agent with a labeled indication for the treatment of ADHD by the FDA: dextroamphetamine, methylphenidate, mixed salts amphetamine or atomoxetine: • Stimulants are highly efficacious and are first-line • Methylphenidate and amphetamine agents are equally efficacious in the

treatment of ADHD • Long-acting formulations are equally efficacious as immediate-release agents but

may be more convenient • In patients with treatment-refractory disease, behavior therapy and/or the use of

medications not approved by the FDA for the treatment of ADHD (bupropion or tricyclic antidepressants) should be considered

• All patient should be monitored for treatment-emergent side effects and assessed periodically for treatment efficacy

• Patients treated with medication for ADHD should have height and weight monitored throughout treatment

• Treatment of ADHD should continue as long as symptoms remain present and cause impairment

American Academy of Child and Adolescent Psychiatry (AACAP)

Psychopharmacological treatment for very young children: contexts and guidelines; 200768

Steps of the algorithm: • First-line: methylphenidate • Second-line: amphetamine • Third-line option: atomoxetine

Institute for Clinical Systems Improvement (ICSI)

Diagnosis and Management of Attention Deficit Hyperactivity Disorder in Primary Care for School-Age Children and Adolescents; 201261

Medication therapy • Use FDA-approved treatments for ADHD in children, including psychostimulants

and/or non-stimulants • Decision to initiate medication therapy should be made in conjunction with

parents and discussion of expected benefits and potential risks • Age, disease severity, and presence of comorbidities should be considered • Optimal medication management alone is superior to other modalities for the

core symptoms of ADHD • If patient does not respond to initial medication choice, a second or third trial with

other stimulants is recommended • Atomoxetine is recommended in patients with comorbid anxiety, sleep initiation

disorder, substance abuse, or tics • Extended-release guanfacine and extended-release clonidine have a labeled

indication as adjunctive therapy with stimulant medications • Second-line medications for ADHD therapy include tricyclic antidepressants

(imipramine, desipramine), alpha adrenergic agonist (clonidine), a nontricyclic antidepressant (bupropion), or immediate-release guanfacine

Abbreviations: ADHD, attention deficit hyperactivity disorder; CADDRA, Canadian ADHD Resource Alliance; CBT, cognitive behavioral therapy

22

Pharmacology The full pathophysiology of ADHD is not well understood; however, evidence suggests that ADHD may be due to inadequate production of catecholamines such as norepinephrine and dopamine in the prefrontal cortex.69-71 Stimulants are used to increase the availability of these catecholamines, which alleviate ADHD symptoms.56 Many different formulations exist, ranging from immediate release to extended release formulations.54,63,72 Duration of action ranges from 3 to 6 hours with IR formulations to 6 to 16 hours with ER formulations. Individual patient genetic variations can result in differences in efficacy between the agents; for example, patients with a 9/9 genotype of the dopamine transporter gene (SLC6A3/DAT1) may require higher doses of stimulant medications in order to achieve adequate symptom control.73

Amphetamines belong to the class of β-phenethlylamines and are potent noncatecholamine sympathomimetic amines.56,72 They increase the availability of catecholamines such as dopamine or norepinephrine via increased release or reuptake inhibition.1,2,12,13 Increased levels of catecholamines result in stimulation of the peripheral and CNS systems and increase of blood pressure and bronchodilation.1,2,8,12,13 The alerting and anorectic effects of amphetamines are thought to be due to norepinephrine release in central noradrenergic neurons. Chemically, amphetamine is composed of 2 active isomers, dextro- or d-amphetamine and levo- or l-amphetamine, which have different actions in the body. High doses of dextro-amphetamine act mainly on dopamine and are approximately 3-4 times more potent than levo-amphetamine in producing CNS stimulation.74 Levo-amphetamine acts mainly on norepinephrine at low doses and has slightly more potent cardiovascular and peripheral effects compared to dextro-amphetamine.74 As a result, some amphetamine products and mixed amphetamine salts utilize higher ratios of dextro-amphetamine to levo-amphetamine (Adzenys 3:1, Dyanavel 3.2:1, and Adderall 3:1) to reduce the risk of unwanted cardiovascular effects. Dextroamphetamine (Dexedrine) and lisdexamfetamine (Vyvanse, an inactive prodrug hydrolyzed by red blood cells and converted to dextro-amphetamine) are not mixed-isomer agents and have pharmacological effects solely due to dextro-amphetamine.51,72,75

Methamphetamine (Desoxyn) or N-methylamphetamine has a chemical structure similar to amphetamine.76 It exists in 2 different active isomers, d-methamphetamine and l-methamphetamine. D-methamphetamine is 3 to 5 times more potent than l-methamphetamine. Methamphetamine works by increasing the availability of catecholamines (dopamine, noradrenaline, and serotonine), enhancing release from storage sites, inhibiting reuptake through monoamine transporters, and decreasing metabolism by inhibiting oxidases.76 The central effects of methamphetamine are more prominent than those of amphetamine due its lipophilic nature.77

Methylphenidate is also structurally related to amphetamines, with the addition of a piperidine group. Methylphenidate exists as 2 active isomers, d- and l-threo methylphenidate. Methylphenidate products may contain only the d-threo isomer (or dexmethylphenidate), or a racemic mixture of the 2 isomers.6,7,17-19 Dexmethylphenidate is more potent than l-methylphenidate. Methylphenidate works by decreasing dopamine and norepinephrine reuptake and, overall, exhibits similar pharmacological properties as amphetamines.72,78

Regarding the mechanism of sustained action with long-acting formulations, some products use specific technologies to produce a fast onset of action followed by a gradual release of the active ingredient. For

23

instance, some formulations contain biphasic release systems that allow a first peak of plasma concentration due to the content in immediate-release active ingredient and a second peak due to the content in delayed-release active ingredient.7,17-19,23,28,30 Other formulations are designed as osmotic delivery systems with amounts of immediate release active ingredient and amounts of osmotic components to control the rate of drug delivery.19,28

Table 4 includes pharmacokinetic properties, type of formulation, and frequency and mode of administration of the CNS stimulants.

24

Table 4. Pharmacokinetic Properties and Other Considerations for Central Nervous System Stimulant Agents1-30,72

Agents Brand Name Preparations Type of Formulation

Content in Active Ingredients

Frequency and Mode of Administration Tmax

Duration of Action Half-life Metabolism &

Excretion Am

phet

amin

e

Adzenys ER ER oral suspension

LA (contains equal amounts of IR and ER AMP)

3 to 1 ratio of d- to l-amphetamine

Once daily 5 h NR 11-13 h (d-amp); 14-15 h (l-amp)

Metabolism: Hepatic via oxidation, deamination, and CYP2D6 Excretion: Urine

Adzenys XR-ODT ER ODT

LA (contains 50% IR and 50% ER AMP)

3 to 1 ratio of d- to l-amphetamine

Once daily (as a whole tablet) 5-8 h 10-12 h

9-11 h (d-amp); 10-14 h (l-amp)

Dyanavel XR ER oral suspension

LA (amounts of IR and ER AMP not specified)

3.2 to1 ratio of d- to l-amphetamine

Once daily 4-4.5 h NR 10-12 h (d-amp); 12-15 h (l-amp)

Amph

etam

ine

sulfa

te

Evekeo Oral tablet SA

Ratio of d- to l-amphetamine sulfate not specified

Once or twice daily 4 h 4-6 h 12 h

Evekeo ODT ODT

SA 1 to 1 ratio of d- to l-amphetamine sulfate

Once or twice daily (as a whole tablet) 3-3.5 h NR 10 h (d-amp);

12 h (l-amp)

Dexm

ethy

lphe

nida

te

hydr

ochl

orid

e

Focalin Oral tablet

SA Dex-methylphenidate hydrochloride

Twice daily 1-1.5 h 3-5 h 2-3 h Metabolism: Extensive metabolism via de-esterification to PPAA (minimal or no pharmacological activity) Excretion: Excreted primarily in the urine

Focalin XR ER oral capsule

LA (capsules with bi-modal release profile. Each capsule contains 50% of DEXMPH dose as IR beads and 50% as enteric-coated, delayed-release beads

Dex-methylphenidate hydrochloride

Once daily

1.5 h (first peak) 6.5 h (second peak)

9-12 h NR

Dext

ro-

amph

etam

ine

Dexedrine Spansule SR oral capsule

LA DEXAMP sulfate Once or twice daily 8 h 8 h 12 h

Metabolism: Hepatic via CYP monooxygenase and glucuronidation Excretion: Urine

25






Excretion De

xtro

amph

etam

ine

Generic DEXAMP sulfate Oral tablet Oral solution

SA DEXAMP sulfate Once or twice daily 3 h 4-6 h 12 h

Metabolism: Hepatic via CYP monooxygenase and glucuronidation Excretion: Urine

ProCentra Oral solution Zenzedi Oral tablet

Dext

roam

phet

amin

e/

Amph

etam

ine

mix

ed sa

lts

Generic DEXAMP/AMP 5, 7.5, 10, 12.5, 15, 20, 30 Oral tablet

SA

Equal amounts of AMP aspartate, AMP sulfate, DEXAMP saccharate, and DEXAMP sulfate (3 to 1 ratio of d- to l-AMP base equivalent)

Once or twice daily 3 h NR

10-11 h (d-AMP) 12-14 h (l-AMP)

Metabolism: Hepatic via oxidation, deamination, and CYP2D6 Excretion: Urine

Adderall XR 5, 10, 15, 20, 25, and 30 ER oral capsule

LA

Equal amounts of AMP aspartate, AMP sulfate, DEXAP saccharate, and DEXAMP sulfate (3 to 1 ratio of d- to l-AMP base equivalent)

Once daily 7 h 6-8 h

9-11 h (d-AMP) 11-13 h (l-AMP)

Mydayis ER oral capsule

LA

AMP aspartate, AMP sulfate, DEXAMP saccharate, and DEAMP sulfate (different strengths compared to Adderall XR)

Once daily 7-10 h NR

10-11 h (d-AMP) 10-13 h (l-AMP)

26






Excretion

Lis-

de

xam

feta

min

e di

mes

ylat

e Vyvanse Oral capsule Oral chewable tablet

LA Lis-dexamfetamine dimesylate

Once daily

1 h (LISDEX) 4 h (DEXAMP)

8-13 h

<1 (LISDEX) 10-13 h (DEXAMP)

Metabolism: LISDEX is hydrolyzed by red blood cells to DEXAMP Excretion: excreted primarily in urine

Met

ham

phet

amin

e

Desoxyn Oral tablet

SA Methamphetamine hydrochloride

Once or twice daily NR NR 4-5 h

Metabolism: Mainly hepatic (aromatic hydroxylation, N-dealkylation and deamination). Seven metabolites identified in the urine Excretion: primarily in the urine

Met

hylp

heni

date

Adhansia XR ER oral capsule

LA (capsules containing multilayered beads, with one IR layer containing 20% of MPH dose and an ER layer with 80% of MPH dose)

Methylphenidate hydrochloride (racemic mixture of d- and l-isomers)

Once daily (swallow capsule as a whole or sprinkled into food. Do not crush or chew)

1.5 h (first peak) 12 h (second peak)

NR 7 h

Metabolism: Extensive metabolism via de-esterification to PPAA (minimal or no pharmacological activity) Excretion: The majority of MPH dose is excreted in the urine. Minimal fecal excretion

Aptensio XR ER oral capsule


Once daily (swallow capsule as a whole or sprinkled into food)

2 h (first peak) 8 h (second peak)

≤16 h 5 h

27






Excretion M

ethy

lphe

nida

te

Concerta ER oral tablet

LA, OROS formulation (tablet with an IR drug overcoat and 3 additional layers: 2 drug layers and 1 layer containing osmotic components)


Once daily (swallow tablet as a whole. Do not crush or chew)

1 h (initial peak) 6-10 h (mean peak)

8-12 h 3.5 h


Cotempla XR-ODT ER ODT

LA (tablets containing 25% IR and 75% ER MPH)

Once daily (Place the whole tablet under the tongue. Do not crush or chew)

5 h NR 4 h

Daytrana ER transdermal patch

LA (adhesive-based matrix transdermal system)

Methylphenidate (racemic mixture of d- and l-isomers)

Apply 2 hours before the effect is needed and remove 9 hours after application

8-10 h 11-12 h 4-5 h (d-MPH); 1-3 h (l-MPH)

Jornay PM ER oral capsule

LA (capsules containing beads with a delayed-release layer and an ER layer)


Once daily (swallow capsule as a whole or sprinkled into food)

14 h (single peak) NR 5.9 h

Metadate CD ER oral capsule


Once daily

1.5 h (first Tmax) 4.5 h (second Tmax)

6-8 h 6.8 h

Metadate ER ER oral tablet

LA

2 or 3 times daily (swallow whole tablet. Do not crush or chew)

NR 8 h NR

Methylin Oral solution

SA 2 or 3 times daily 1-2 h 3-5 h 2.7 h

28






Excretion M

ethy

lphe

nida

te

Quillichew ER ER oral chewable tablet

LA (tablets containing 30% IR and 70% ER MPH)


Once daily 5 h NR 5.2 h


Quillivant XR ER oral suspension

LA (oral suspension containing 20% IR and 80% ER MPH)

Once daily 5 h NR 5.6 h (d-MPH)

Relexxii ER oral tablet

LA (tablets with an IR drug overcoat and an osmotic system that delivers MPH gradually)

Once daily (swallow the whole tablet. Do not crush or chew)

1 h (first Tmax) 6-10 h (second Tmax)

12 h NR

Ritalin Oral tablet

SA 2 or 3 times daily 1.9 h (0.3 to 4.4 h) 3-5 h

2.5-3.5 h (1.3-7.7 h) Ritalin LA

ER oral capsule

LA (capsules with bi-modal release profile. Each capsule contains 50% of MPH dose as IR beads and 50% as enteric-coated, delayed-release beads)

Once daily (swallow the whole capsule or sprinkle into food. Do not crush or chew)

1-4 h (first Tmax) 4-11 h (second Tmax)

6-8 h

Note: Gray shaded text highlights new FDA approved products or formulations identified since the publication of the 2016 P&T report on ADHD stimulants Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMP, amphetamine; DEXAMP, dextroamphetamine; DEXMPH, dexmethylphenidate; ER, extended release; IR, immediate release; h, hour; LA, long acting; LISDEX, lisdexamfetamine; MPH, methylphenidate; NR, not reported; ODT, orally disintegrating tablet; OROS, osmotic release oral system; PPAA; alpha-phenyl-piperidine acetic acid; SA, short acting; Tmax, time to maximum concentration; XR, extended release

29

Table 5. Special Population Considerations for Central Nervous System Stimulant Agents1-30,72 Agent Pediatrics Geriatrics Renal & Hepatic Impairment Pregnancy & Lactation

Amphetamine-Containing Products Amphetamine (Adzenys ER, Adzenys XR-ODT; Dyanavel XR; Evekeo, Evekeo ODT) Efficacy and safety established in

children ≥ 3 years old (Dexedrine, Procentra, or Zenzedi)

Efficacy and safety established in

children ≥ 6 years old (all amphetamine products, Dexedrine

Spansule, Adderall, Adderall XR, Vyvanse, and Desoxyn)

Efficacy and safety established in children ≥ 13 years old (Mydavis)

Evekeo and Adderall (generic) labeling

states: “Amphetamines are not recommended for use in children < 3

years of age with ADHD”4

No studies in elderly patients

No renal or hepatic adjustment reported in the manufacturer’s

labeling

Pregnancy: May cause fetal harm

Lactation: Breastfeeding

not recommended

Dextro-amphetamine (Dexedrine Spansule, Dexedrine, ProCentra, Zenzedi)

No renal or hepatic adjustment reported in the manufacturer’s

labeling

Dextro-amphetamine-Amphetamine Mixed Salts (Adderall, Adderall XR, Mydayis)

Adderall XR: dosage adjustments in patients with severe renal

impairment. Not recommended in ESRD


Insufficient data on elderly patients

Renal: Severe renal impairment: max dose

(50 mg/day) ESRD: max dose (30 mg/day)

Hepatic: No hepatic adjustment reported in

the manufacturer’s labeling Methamphetamine (Desoxyn) No renal or hepatic adjustment

reported in the manufacturer’s labeling

Methylphenidate-Containing Products Dex-methylphenidate (Focalin, Focalin XR)

Efficacy and safety established in children ≥ 6 years old

No studies in elderly patients

No experience with the use of these agents in patients with renal or

hepatic impairment

Pregnancy: These agents should be used during pregnancy only if the

potential benefit justifies the potential risk to the

fetus

Lactation: Caution should be exercised

Methylphenidate (Adhansia XR, Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana, Jornay PM, Metadate CD, Metadate ER, Methylin, QuilliChew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA)

No studies in patients > 72

years old

Abbreviations: ER, extended release; ESRD, end stage renal disease; ODT, orally disintegrating tablet; XR, extended release

30

Comparative Efficacy and Safety Evidence The previous 2016 Utah Medicaid Pharmacy and Therapeutics (P&T) Committee drug class review on Central Nervous System Stimulants used in the Treatment of Attention Deficit Disorder included a summary of the results provided by the Oregon DERP Drug Class Review on Pharmacological Treatments for Attention Deficit Hyperactivity Disorder (October 2009). The P&T report additionally included the results from SRs and RCTs identified in a literature search in PubMed and the Cochrane Library from January 2009 to April 2016. The current P&T report provides comparative efficacy and safety evidence to update the previously published P&T report.

Our literature search yielded 630 unique titles, of which 3 SRs and 3 RCTs (in 5 publications) evaluating the comparative efficacy and safety of the ADHD stimulants listed in Table 1 met inclusion criteria for the qualitative synthesis. Figure 1 shows the PRISMA flow diagram for the review process of SRs and RCTs.

Figure 1. PRISMA Flow chart for Publication Screening

Abbreviations: DERP; Drug Effectiveness Review Project; RCT, randomized controlled trials; SR, systematic review a See Appendix B for a list of excluded studies b Five publications, including 3 systematic reviews (in 3 publications)66,79,80 and 3 randomized controlled trials (in 2 publications)81,82

Records excluded (598)

Full-text articles assessed for eligibility

(32)

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

tific

atio

n • Records identified in Ovid Medline: 168 SRs + 243 RCTs

• Records identified in Embase: 253 SRs + 270 RCTs

Records after duplicates removed (300 SRs + 38 Epistemonikos results + 292 RCTs)

Full-text articles excluded, with reasonsa

(27) Wrong study design (15) Wrong comparator (8)

Wrong outcome (1) More up-to-date SR available (1)

Only abstract available (1) SRs reporting an absence of

comparative evidence (1) Publications included in qualitative synthesis (5b)

Additional records identified through other sources: 153 results from Epistemonikos and 1 report from Oregon DERP

Records screened (630)

31

Appendix C includes key findings reported in the SRs and RCTs identified from the literature search.

Following are 3 sections concerning the clinical evidence identified in the literature search. Section 1 contains a summary of key findings. Section 2 includes detailed information regarding head-to-head SRs and RCTs. Section 3 includes a summary of an AHRQ report published in 2018 that searched for long-term head-to-head RCTs and did not find any.

Section 1. Summary of the Most Current Efficacy and Safety Head-to-Head Evidence Among ADHD Stimulants in Children, Adolescents, and Adults

Comparative evidence among ADHD stimulants is limited and of fair-quality. The majority of the identified trials included children and adolescents (6 to 17 years of age), had small sample size, and were of short duration (< 6 months). No ADHD stimulant formulation is clearly superior to another regarding efficacy and safety in children, adolescents, and adults with ADHD. Some RCTs did not find significant differences among ADHD stimulants and others showed inconsistent results depending on the ADHD rating scales utilized, dose comparisons, or time point of efficacy assessment (morning, afternoon, or evening). Although some preparations are similarly efficacious, they may differ in the mode of delivery, pharmacokinetic profile, dosing, duration of action, and adverse events. Clinicians should individualize ADHD treatment based on patient´s age, coexisting conditions, symptom profile, abuse or diversion potential, social stigma, compliance, cost, and family or patient preferences.

Comparative evidence in young children (< 5 years) and long-term comparative evidence in all age groups is not available.

Section 2. Comparative Evidence from the Systematic Reviews and Randomized Controlled Trials

Summary of the Oregon DERP Drug Class Review on Pharmacologic Treatments for Attention Deficit Hyperactivity Disorder (July 2015)79

Young Children (3-5 years)

No head to comparisons among ADHD stimulants were identified.

Children (6 to 12 years) and mixed population up to 18 years

Most of the efficacy and safety evidence identified included children with ADHD and compared 1) IR versus ER methylphenidate, 2) IR methylphenidate versus IR dexamphetamine or IR MAS, and 3) lisdexamfetamine versus ER methylphenidate. Single trials are available for other comparisons (eg, methylphenidate transdermal system versus IR methylphenidate, osmotic release oral system [OROS] methylphenidate versus ER MAS, or lisdexamfetamine versus ER MAS). Overall, moderate to low-quality evidence showed similar efficacy among ADHD stimulants, with the exception of a few differences in terms of ADHD symptom improvement (as described in the “Summary of evidence” from the Oregon DERP Drug Class Review):

- Based on low-quality evidence (post-hoc comparisons), lisdexamfetamine may be superior to OROS methylphenidate in terms of ADHD symptom improvements (ie, ADHD-rating scale-IV score and parent score improvements); however, more discontinuations and more adverse events (insomnia, nausea, decreased appetite and weight) were reported with

32

lisdexamfetamine. Higher incidence of headaches and nasopharyngitis were observed with OROS methylphenidate.

- Studies comparing OROS methylphenidate versus IR methylphenidate showed conflicting efficacy results (double-blind studies showed no differences between groups and open-label studies showed better symptom improvements with OROS methylphenidate).

- Limited evidence suggested superiority of methylphenidate LA vs. methylphenidate OROS; however, this was shown for some efficacy outcomes (not all).

- Limited evidence from studies comparing different stimulant preparations (ie, methylphenidate OROS vs. methylphenidate CD; dexmethylphenidate ER vs. methylphenidate OROS, dextroamphetamine IR vs. dextroamphetamine SR, and dextroamphetamine SR vs. MAS) showed different efficacy results depending on the time of assessments (morning, afternoon, and evening). This may be associated with the different pharmacokinetic profiles.

Adolescents (12 to 18 years)

Limited moderate to low-quality evidence is available in adolescents, with only 1 head to head trial reporting no differences in ADHD symptom improvements between MPH OROS and MAS IR and the other trial not reporting on this efficacy outcome. Both trials reported on driving performance and showed better results with methylphenidate OROS compared to MAS IR or methylphenidate IR.

Adults (≥ 18 years)

Limited and low-quality evidence is available in adults, with only 2 head to head trials identified. Overall, evidence suggested similar ADHD symptom improvement and adverse event rates for IR methylphenidate versus OROS methylphenidate (switching study) and IR MAS versus ER MAS.

Comorbidities and Abuse, Misuse, or Diversion

No head to head RCTs on abuse, misuse or diversion were identified. Only observational data is available.

In patients with ADHD and anxiety, head to head evidence reported no differences among stimulants in the incidence of anxiety. No direct evidence was identified in patients with other comorbidities (eg, tics disorders, seizures, and suicidal behavior).

Table 6 displays a summary of the head-to-head efficacy evidence found in children, adolescents, and adults, based on evidence summarized in the 2015 Oregon DERP Drug Class Review.

33

Table 6. Head-to-Head Randomized Controlled Trials Among FDA-Approved Stimulant Agents for ADHD79

Generic Name Number of Head-

to-Head RCTs (Population)

Summary of Results Strength of evidence

MPH ER vs. MPH IR

7 (children) 1 (adolescents)

1 (adults)

Children: - IR MPH vs. OROS MPH (Concerta): conflicting

results (3 studies did not show significant differences on ADHD symptom improvement and 2 trials found significant differences for some efficacy assessments in favor of MPH ER) [5 trials]

- IR MPH vs. MPH SR (Ritalin SR): mixed results (physician scores indicated no efficacy differences, teacher questionnaires favored IR MPH, and parent questionnaires favored MPH SR) [1 small trial]

- IR MPH vs. MPH ER (Metadate CD): non-inferiority was demonstrated using the Conners’ IOWA teachers rating scale [1 trial]

Adolescents: MPH OROS (Concerta) was better than IR MPH in terms of simulated driving performance at evening and night [1 study] Adults: No differences in ADHD symptom improvement between continuing MPH IR vs. switching to MPH OROS [1 fair-quality switching study]

Moderate to low quality evidence

MPH TS vs. MPH IR 1 (children)

No significant efficacy differences between groups (using math assessment and teacher’s IOWA scale) [1 trial]

Small, fair-quality study

MPH TS vs. MPH OROS

1 (children) No significant efficacy differences between groups (using ADHD rating scale and Conners’ scale) [1 trial]

Fair-quality study. Study may be unpowered to detect differences between groups

MPH ER vs. MPH ER

3 (children)

MPH OROS (Concerta) vs. MPH CD (Metadate CD): different efficacy results (using SKAMP deportment and attention scale scores) depending on the time of assessment (morning, afternoon, or evening) [1 study] MPH OROS (Concerta) vs. MPH LA (Ritalin LA): MPH LA was superior to MPH OROS on some efficacy outcomes (using SKAMP scale), but not all [2 small studies]

Fair-quality studies

DEXAMP IR vs. MPH IR

9 fair-quality studies (children)

No significant efficacy differences between groups based on children’s self-assessment and parent or teacher assessment [8 of 9 fair-quality studies]

Fair- to poor- quality studies

DEXMPH ER vs. MPH ER

2 (children)

DEXMPH vs. MPH OROS (Concerta): different efficacy results (based on SKAMP scale scores and math scores) depending on the time of assessment (2 small studies)

Fair-quality studies

34

Table 6. Head-to-Head Randomized Controlled Trials Among FDA-Approved Stimulant Agents for ADHD79

Generic Name Number of Head-

to-Head RCTs (Population)

Summary of Results Strength of evidence

MAS IR vs. MPH IR

3 fair-quality + 2 poor-quality

studies (children)

MAS IR was significantly better vs. MPH IR for some efficacy endpoints (children’s assessment and CGI-S), but not all. Results were different depending on the studied dose

Fair-to poor- quality studies

MAS IR vs. DEXAMP IR vs. DEXAMP SR

1 (children)

DEXAMP IR showed better efficacy compared to DEXAMP SR (morning efficacy assessment). DEXAMP SR showed better efficacy compared to MAS IR (afternoon efficacy assessment)

Fair-quality study

MAS IR vs. MPH ER

1 (adolescents) No differences in ADHD symptom improvement. MPH OROS was better than MAS IR (outcome: simulated driving performance)

Moderate-quality evidence

MAS XR vs. DEXMPH ER

2 (children) 1 study showed no significant efficacy differences between groups (based on ADHD rating scale and CGI-S)

Small, fair-quality study

MAS XR vs. MAS IR 1 (adults) No differences in ADHD symptom improvement Fair-quality study

LISDEX vs. MPH ER 1 (children)

LISDEX vs. MPH OROS (Concerta): 1 post hoc comparison: - LISDEX superior to MPH OROS (endpoint: ADHD-RS-

IV score improvements from baseline to week 7) - LISDEX superior to MPH OROS (endpoint: Conners´

parent rating scale improvements)

Fair-quality evidence

LISDEX vs. MAS XR

1 (children) 1 RCT found no significant efficacy differences between groups (based on SKAMP scale scores)

Small, fair-quality trial

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CGI-S, clinical global impression scale; DEXAMP, dextroamphetamine; DEXMPH, dexmethylphenidate; ER or XR, extended release; IR, immediate release; LISDEX, lisdexamfetamine; MAS, mixed amphetamine salts; MPH, methylphenidate; OROS; osmotic-release oral system; RCT, randomized controlled trials; RS, rating scale; SKAMP, Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale; TS, transdermal system

Additional evidence not included in the Oregon DERP Drug Class Review or AHRQ report

- Amphetamine vs. Methylphenidate

Cortese et al (2018) performed a network meta-analysis and a pairwise meta-analysis of RCTs (≥ 1 week´s duration) comparing ADHD medications in children ≥ 5 years, adolescents, or adults with ADHD.66 In children and adolescents, results of the direct meta-analyses showed a significantly greater efficacy on ADHD core symptoms as rated by clinicians at week 12 and a significantly better result on the Clinical Global Impression (CGI) scale at week 12 with amphetamines (including lisdexamfetamine) compared to methylphenidate (formulation type not specified). However, some tolerability outcomes (discontinuation due to adverse events) and mean change in body weight significantly favored methylphenidate compared to amphetamines. Other outcomes (systolic blood pressure, diastolic blood pressure, and acceptability) revealed no differences between amphetamines and methylphenidate. Data in adult populations and long-term data in all populations were insufficient.66

35

- Lisdexamfetamine vs. Methylphenidate

Luan et al (2017) completed a network meta-analysis and a pairwise meta-analysis of RCTs (≥ 3 week´s duration) comparing ADHD medications in children and adolescents (6 to 18 years) with ADHD.80 The direct meta-analysis reported significantly worse scores on the ADHD rating scale (ADHD-RS) with methylphenidate (formulation type not specified) compared to lisdexamfetamine. With regard to safety endpoints (ie, all-cause withdrawal, withdrawal due to adverse events, withdrawal due to lack of efficacy, and abdominal pain), no significant differences were reported between methylphenidate and lisdexamfetamine.80 Authors highlighted that only a few head-to-head RCTs are included and that further well-designed RCTs should be conducted.80

Newcorn et al (2017) conducted 2 head-to-head RCTs (one flexible-dose trial and one forced-dose trial) of lisdexamfetamine compared to OROS methylphenidate in adolescents with ADHD.82 The forced-dose trial randomized patients to lisdexamfetamine (initial dose: 30 mg/day; then specific dosage titration until a maximum dose of 70 mg/day) or OROS methylphenidate (initial dose: 18 mg/day; then specific dosage titration until a maximum dose of 72 mg/day). In the flexible-dose study patients were randomized to lisdexamfetamine (initial dose: 30 mg/day) or OROS-MPH (initial dose: 18 mg/day). Dosages could be increased at weekly intervals until optimal dose was achieved. The primary endpoint was the change in ADHD rating scale IV total score from baseline to end of study (6 to 8 weeks depending on the study type). The key secondary endpoint, percentage of patients with improvement on the Clinical Global Impression-Improvement scale (CGI-I) at the end of treatment. Results from the primary and key secondary endpoints were significantly better with lisdexamfetamine compared to OROS methylphenidate in the forced-dose trial; however, these results were not statistically significant in the flexible-dose trial.82 In general, both agents were well-tolerated and safety profiles were consistent with prior reports; however, these 2 trials were underpowered to detect safety differences between groups.82 Authors stated that these findings were not unexpected due to the trial designs. Forced-dose studies generally detect differences better than flexible-dose studies because patients usually receive the optimal dose and no subjective clinical judgement is involved in dosage titration. Authors commented that findings support treatment guideline recommendations regarding the use of amphetamines or methylphenidate formulations as first-line treatments for adolescents with ADHD.82

- Immediate release methylphenidate (IR MPH) vs. osmotic-release oral system methylphenidate (OROS MPH)

Chou et al (2018) conducted a prospective, single-arm, open-label, 8-week, multicenter study to assess the efficacy of switching from IR MPH to OROS MPH (flexible dose) in ADHD patients 6 to 18 years.81 After switching to OROS MPH, patients had significant improvements on ADHD symptoms from baseline to 3 follow-up visits (2, 4, and 8 weeks), as rated by parents, teachers, and study investigators using the Swanson, Nolan, and Pelham version IV (SNAP-IV) and Clinical Global Impression (CGI) scales.81 Significant improvements in 3 of the 4 dimensions of a social functioning questionnaire were reported. In addition, mental health status of patients’ mothers was improved; however, fathers’ mental health did not improve.81

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Section 3. Relevant Systematic Reviews Searching for Head-to-Head Evidence

Summary of the AHRQ report on Attention Deficit Hyperactivity Disorder: Diagnosis and Treatment in Children and Adolescents (January 2018)83

The 2018 AHRQ report evaluated the long-term efficacy and safety (≥ 6 months) among FDA-approved medications for children and adolescents with ADHD.83 No long-term RCTs comparing ADHD stimulants were identified. Some observational studies reporting head-to-head safety outcomes (eg, growth suppression) between amphetamines and methylphenidate were found in the previous 2011 AHRQ report; however, these results were inconclusive.84 Authors concluded that evidence is insufficient to determine whether there are long-term efficacy and safety differences among ADHD stimulants.83

37

Safety Central nervous system (CNS) stimulants exert their effects via increasing the availability of catecholamines in the synaptic cleft.31 As a result, side effects tend to be similar across the drug class. The most common adverse events (based on events occurring in ≥10% of patients) include headache, insomnia, increased blood pressure, abdominal pain, and decreased appetite.1-30 Less common adverse events reported with the CNS stimulants include restlessness, anxiety, dizziness, weight loss, growth suppression in children and adolescents, changes in libido, dry mouth, nausea, vomiting and diarrhea.1-30 The stimulant agents are Schedule II controlled substances due to high potential for abuse. Product labeling includes a black box warning for high dependence and abuse potential. Close monitoring and caution should be exercised when prescribing to patients with a known history of drug abuse or dependence.1-30 Some of the more serious, but rare, adverse effects reported with the CNS stimulants include psychosis, sudden death, cardiac arrhythmias, stroke, myocardial infarction, priapism, anaphylaxis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Permanent leukoderma has been reported with methylphenidate transdermal patches (Daytrana).1-30,72 See Table 7 and Table 8 for a summary of the warnings and adverse effects (except post-marketing events) reported with CNS stimulants, based on package labeling.

Most studies evaluating the difference in adverse events among the stimulant agents were small, of fair quality, and showed mixed or inconsistent results.79 According to clinical evidence summarized in the 2015 Oregon DERP report, the following results were reported from short-term trials:79

Young children (preschool age; 3-5 years): No head-to-head evidence

Children (6-12 years and mixed populations up to age 18 years):

- No significant differences in adverse event rates were reported between IR dextroamphetamine and IR methylphenidate (4 trials); however, 2 trials revealed larger weight loss with IR dextroamphetamine compared to IR methylphenidate

- No significant differences in adverse event rates were reported between mixed amphetamine salts and IR methylphenidate (1 trial); however, 2 low quality trials showed differences (higher rates of appetite loss and sleep trouble with mixed amphetamine salts)

- No significant differences in adverse event rates were reported between IR and ER methylphenidate formulations (eg, OROS methylphenidate)

- No significant differences in adverse event rates were observed between 2 ER methylphenidate formulations (Ritalin LA and Concerta)

- The incidence of insomnia/trouble sleeping and decreased appetite was significantly higher with methylphenidate OROS versus methylphenidate CD

- Two trials suggested no differences between transdermal methylphenidate and methylphenidate OROS or IR methylphenidate

- No significant differences were reported between ER dexmethylphenidate and methylphenidate OROS in terms of adverse event rate, serious adverse events, or discontinuations due to adverse events (2 small trials)

38

- No significant differences in adverse event rates were reported between dexmethylphenidate ER and mixed amphetamine salts XR (1 small study)

- One trial showed similar incidence of overall adverse events between lisdexamfetamine and methylphenidate OROS. More discontinuations due to adverse events were observed with lisdexamfetamine. Higher rates of insomnia, nausea, decreased appetite, and reduced weight were reported with lisdexamfetamine, while higher incidence of headache and nasopharyngitis were observed with methylphenidate OROS.

Adults:

- One trial showed similar safety profiles between continuing with IR methylphenidate or switching to methylphenidate OROS

Regarding comparative long-term safety, only observational data was found. Low-strength evidence in children and adults suggested no significant differences between amphetamines and methylphenidate in terms of sudden death, ventricular arrhythmia, and emergency department visit rates for cardiac reasons.79 Methylphenidate and amphetamine agents may also be associated with weight loss (or reduced weight gain compared to control) and delayed growth in children. Regarding weight gain suppression, moderate-quality evidence showed that IR dextroamphetamine leads to a greater weight gain suppression compared to IR methylphenidate in the first 1-2 years; however, this difference resolved after 2 years.79 No differences were found in height and weight change over 3 years of treatment between IR methylphenidate and mixed amphetamine salts. Regarding the incidence of adverse events such as insomnia and decreased appetite, evidence suggested similar rates among IR methylphenidate, methylphenidate OROS, MAS, and MAS XR. Tics are reported with both methylphenidate and amphetamine agents, but no differences were reported over 2 years between IR methylphenidate, methylphenidate OROS, and MAS XR.79

A growing concern with stimulant therapy is the increasing rate of stimulant abuse which occurs among the caretakers of children receiving the medication and youth without diagnoses of ADHD in addition to the patients themselves. In youth without an ADHD diagnosis, the most frequently reported reason for abuse is improved academic achievement.85 Along with the increased rates of abuse come increased rates of overdose. Stimulant medications have a low therapeutic index, with toxicity occurring at levels just above recommended doses. In general, acute ingestion of more than 1 mg/kg of dextroamphetamine (or equivalent) may be life-threatening; although the development of tolerance can occur after repeated stimulant use. Acute signs of stimulant overdose include restlessness, agitation, psychosis, seizures, coma, and hypertension potentially resulting in myocardial infarction or intracranial hemorrhage. Other peripheral signs and symptoms may include sweating, tremor or rigidity. Death may occur as a result of ventricular arrhythmia, status epilepticus or hyperthermia. Effects associated with chronic amphetamine abuse include cardiomyopathy, dental changes, paranoid psychosis, pulmonary hypertension, and weight loss.86 The National Poison Data System published a retrospective observational case series of non-therapeutic stimulant exposures from 2007 to 2012. According to the report, the majority of patients were referred to health care facilities with most patients reporting no effects or only minor toxicity. Serious adverse effects occurred in approximately 20-25% of reported cases and toxic effects were similar across all stimulant agents.87 According to the 2015 Oregon DERP report, comparative evidence in terms of abuse, misuse, and diversion is limited and mainly based on survey data.79 Two studies using 2002 and 2009 data from the National Survey on Drug Use and Health

39

indicated that “lifetime nonmedical use” was more common with IR methyphenidate or dextroamphetamine compared with mixed amphetamine salts.79 Another survey suggested amphetamine/dextroamphetamine is the most frequently diverted ADHD prescribed medication among college students. The rate of diversion was similar between methylphenidate and ER methylphenidate.79

Table 7. Warnings and Precautions for the Central Nervous System Stimulant Agents1-30,72

Agent US Black Box Warnings Concerning ADHD Indication Other Warnings and Precautions

Amphetamine (Adzenys ER, Adzenys XR-ODT; Dyanavel XR; Evekeo, Evekeo ODT)

General black box warning for amphetamines and methylphenidate-containing products: CNS stimulants have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy. Specific black box warnings in the labeling of some products: “Pay particular attention to the possibility of subjects obtaining amphetamines for non-therapeutic use or distribution to others; prescribe and dispense the drugs sparingly” (Dextroamphetamine-containing products, methamphetamine) “Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events” (Evekeo only, dextroamphetamine-containing products, Adderall, Adderall XR, methamphetamine) “Stimulants should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior” (Concerta, Daytrana, Metadate CD and Metadate ER) “Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up” (Metadate CD and Metadate ER)

General warnings for amphetamine- and methylphenidate-containing products: - Serious cardiovascular reactions (eg,

sudden death) - Blood pressure and heart rate increases - Psychiatric adverse reactions (eg,

psychotic or manic symptoms) - Long-term suppression of growth - Peripheral vasculopathy, including

Raynaud’s phenomenon Specific warnings in the labeling of some products: - Serotonin syndrome when

amphetamines are combined with agents that affect serotonergic neurotransmitter systems, or during overdosage situations

- Seizures: Stimulants may reduce the convulsive threshold (Evekeo and Evekeo ODT, dextroamphetamine-containing products, MAS, Vyvanse, methamphetamine, Concerta, Metadate CD and Metadate ER, Methylin, Relexxii)

- Visual Disturbance (dextroamphetamine-containing products, Adderall, Adderall XR, methamphetamine, Concerta, Metadate CD, Metadate ER, Methylin, Relexxii)

- Tics: may exacerbate tics (Adderall and Adderall XR)

- Prolonged penile erections or priapism (methylphenidate products)

- GI obstruction with preexisting GI narrowing (Concerta, Relexxii)

- Hematologic monitoring during prolonged therapy (Concerta, Metadate CD, Metadate ER, Relexxii)

- Allergic-Type Reactions FD&C Yellow No. 5 (tartrazine) (Adhansia XR only)

- Risks in Phenylketonurics: QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame (Quillichew ER)

Dextroamphetamine (Dexedrine Spansule, Dexedrine, ProCentra, Zenzedi)

Dextroamphetamine-Amphetamine Mixed Salts (Adderall, Adderall XR, Mydayis)


Methamphetamine (Desoxyn)

Dexmethylphenidate (Focalin, Focalin XR)

Methylphenidate (Adhansia XR, Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana, Jornay PM, Metadate CD, Metadate ER, Methylin, QuilliChew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA)

40

Table 8. Adverse Events Reported with the Central Nervous System Stimulant Agents72

Amphetamine Dex-methylphenidate

Dextro-amphetamine

Dextro-amphetamine

Mixed Salts Lisdexamfetamine Methamphetamine Methylphenidate

CNS

Insomnia (children: 4%), emotional lability (children: 3%), drug abuse, drug dependence

Headache (adults: 26% to 39%; children and adolescents: 25%), insomnia (children and adolescents: 5% to 17%), jitteriness (adults: 12%), anxiety (5% to 11%), dizziness (adults: 6%), irritability (children and adolescents: 2% to 5%), depression (children and adolescents: 3%), emotional lability (children and adolescents: 3%), drug abuse, drug dependence

Aggressive behavior, dizziness, dysphoria, euphoria, exacerbation of tics, Gilles de la Tourette syndrome, headache, insomnia, mania, overstimulation, psychosis, restlessness

Insomnia (ER: 8% to 31%), headache (ER; adults: ≤26%), emotional lability (ER: 2% to 9%), anxiety (ER; adults: 7% to 8%), agitation (ER; adults: 2% to ≤8%), dizziness (ER: 2% to 7%), irritability (6%), fatigue (ER: 2% to 6%), drowsiness (ER: 2% to 4%), speech disturbance (ER: 2% to 4%), twitching (ER: 2% to 4%), depression (3%), jitteriness (2%), aggressive behavior, dysphoria, euphoria, exacerbation of vocal tics, formication, outbursts of anger, overstimulation, paresthesia, psychosis, restlessness, talkativeness

Insomnia (13% to 27%), irritability (children: 10%), anxiety (adults: 5% to 6%), jitteriness (adults: 4% to 6%), dizziness (children: 5%), agitation (adults: 3%), emotional lability (children: 3%), restlessness (adults: 2% to 3%), drowsiness (children: 2%), increased energy (adults: 2%), nightmares (adults: 2%), paresthesia (adults: 2%), tics (children: 2%), outbursts of anger, paranoia, talkativeness

Dizziness, drug dependence (prolonged use), dysphoria, euphoria, exacerbation of tics (motor, phonic, and Tourette's syndrome), headache, insomnia, overstimulation, psychotic symptoms, restlessness

Insomnia (including initial insomnia; oral: 2% to 33%; transdermal: 6% to 13%), headache (2% to 22%), irritability (6% to 11%), emotional lability (1% to 9%), anxiety (oral: 8%), increased diastolic blood pressure (oral: 7%), tics (transdermal: 7%; oral: 2%), dizziness (2% to 7%), psychomotor agitation (oral: 5%), depressed mood (oral: 4%), nervousness (oral: 3%; transdermal: <1%), restlessness (oral: 3%), aggressive behavior (oral: 2%), agitation (oral: 2%), depression (≤2%), hypertonia (oral: 2%), lack of emotion (oral: 2%), vertigo (oral: 2%), confusion (oral: 1%), sedation (oral: 1%), tension (oral: 1%), tension headache (oral: 1%), paresthesia (≤1%), drug abuse, drug dependence, Gilles de la Tourette syndrome (rare), hypervigilance, jitteriness, mood changes, outbursts of anger, panic attack, sleep disorder, toxic psychosis

41



Dextro-amphetamine

Dextro-amphetamine


CV

Not reported Increased blood pressure

Cardiomyopathy, hypertension, palpitations, tachycardia

Systolic hypertension (ER; adolescents: 12% to 35%; dose related; transient), tachycardia (ER; adults: ≤6%), palpitations (ER: 2% to 4%), increased blood pressure, myocardial infarction, Raynaud's phenomenon

Increased heart rate (adults: 2% to 7%), increased blood pressure (adults: 3%), palpitations (2%)

Hypertension, increased blood pressure, palpitations, tachycardia

Tachycardia (oral: 5%; transdermal: ≤1%), palpitations (oral: 3%; transdermal: <1%), increased blood pressure (≥2%), increased heart rate (oral: ≥2%), cardiac arrhythmia, decreased blood pressure, decreased pulse, heart murmur, hypertension, increased pulse

Derma

Not reported Pruritus (children and adolescents: 3%)

Alopecia, urticaria

Diaphoresis (ER: 2% to 4%), skin photosensitivity (ER: 2% to 4%), alopecia, dermatillomania, skin rash, urticaria

Hyperhidrosis (adults: 3% to 4%), skin rash (children: 3%), pruritus (adults: 2%)

Alopecia, urticaria Hyperhidrosis (oral: 5%), excoriation (oral: 4%), skin rash (oral: 2%), macular eruption

Endo&Meta

Not reported Growth suppression, weigth loss

Change in libido, weight loss

Weight loss (ER: 4% to 10%), decreased libido (ER: 2% to 4%), dysmenorrhea (ER: 2% to 4%)

Weight loss (children and adolescents: 9%; adults: 3% to 4%), decreased libido (adults: <2%)

Change in libido, growth suppression (children)

Weight loss (2% to 9%), decreased libido (oral: 2%), growth suppression, hot flash, increased thirst

GI

Decreased appetite (children: 4%), upper abdominal pain (children:

Decreased appetite (children and adolescents: 30%), xerostomia (adults: 7% to 20%), abdominal pain (children and

Anorexia, constipation, diarrhea, unpleasant taste, xerostomia

Decreased appetite (ER: 22% to 36%), xerostomia (ER: 2% to 35%), abdominal pain (ER: 11% to 14%), nausea (ER: 2% to 8%),

Vomiting (children: 9%; adults: 2%), diarrhea (adults: 7%), nausea (6% to 7%), constipation

Constipation, diarrhea, gastrointestinal distress, unpleasant taste, xerostomia

Decreased appetite (2% to 26%), xerostomia (oral: 14%), nausea (2% to 13%), vomiting (2% to 10%), abdominal pain (transdermal: 5% to 7%), upper abdominal pain

42



Dextro-amphetamine

Dextro-amphetamine


4%), abdominal pain (children: 3%), diarrhea

adolescents: 15%), nausea (children and adolescents: 9%), dyspepsia (5% to 9%), vomiting (children and adolescents: 2% to 9%), anorexia (children and adolescents: 5% to 7%)

vomiting (ER: 2% to 7%), diarrhea (ER: 2% to 6%), constipation (ER: 2% to 4%), dyspepsia (ER: 2% to 4%), teeth clenching (ER: ≤4%), tooth infection (ER: ≤4%), anorexia (ER: 2%), bruxism (2%), unpleasant taste

(adults: 6%), anorexia (2% to 5%), gastroenteritis (adults: 2%)

(oral: 6%), anorexia (2% to 5%), bruxism (oral: 2%), dyspepsia (oral: 2%), motion sickness (oral: 2%), constipation (oral: 1%), abdominal distress, diarrhea

GU

Not reported Priapism Frequent erections, impotence, prolonged erection

Urinary tract infection (ER: 5%), upper abdominal pain (adolescents: 4%), impotence (ER: 2% to 4%), erectile dysfunction (2%), frequent erections, prolonged erections

Erectile dysfunction (adults: 3%)

Frequent erections, impotence, prolonged erection

Erectile dysfunction

NMS Not reported Rhabdomyolysis Dyskinesia,

rhabdomyolysis, tremor

Dyskenesia, rhabdomyolysis, tremor

Tremor (adults: 2%)

Rhabdomyolysis, tremor

Back pain (oral: 3%), tremor (oral: 3%), asthenia, muscle spasm

Ophth Not reported Not reported Accommodation

disturbances, blurred vision

Blurred vision, mydriasis

Not reported Not reported Blurred vision (≤2%), eye pain (oral: 2%), dry eye syndrome

Resp

Allergic rhinitis (children: 4%), epistaxis (children: 4%)

Pharyngolaryngeal pain (adults: 4% to 7%), nasal congestion

Not reported Dyspnea (ER: 2%-4%)

Dyspnea (adults: 2%), oropharyngeal pain (2%)

Not reported Nasopharyngitis (oral: 3%), streptococcal pharyngitis (oral: 3%), cough (oral: 2%), upper respiratory tract

43



Dextro-amphetamine

Dextro-amphetamine


(children and adolescents: 5%)

infection (oral: 2%), oropharyngeal pain (oral: 1% to 2%), dyspnea, sinusitis

Misc

Accidental injury (children: 3%)

Fever (children and adolescents: 5%)

Not reported Fever (ER: 5%), accidental injury (children and adolescents: 4%), anaphylaxis, angioedema, hypersensitivity reaction

Fever (children 2%)

Not reported Bruise (oral: 3%), fever (oral: 2%), anemia, leukopenia, increased serum alanine aminotransferase

Abbreviations: CNS, central nervous system; CV, cardiovascular; Derma, dermatologic; Endo&Meta, endocrine and metabolic; ER, extended-release; GI, gastrointestinal; GU, genitourinary; Misc, miscellaneous; NMS, neuromuscular and skeletal; Resp, respiratory; Ophth, ophthalmic; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis

44

Summary There are currently seven CNS stimulant agents available in the US, including amphetamine, dexamphetamine, dexmethylphenidate, lisdexamfetamine, methamphetamine, methylphenidate, and mixed dextroamphetamine-amphetamine salts. The CNS stimulant agents are indicated for the treatment of ADHD and some are additionally indicated for the treatment of exogenous obesity, narcolepsy, or binge-eating disorder.

ADHD therapy includes stimulant or nonstimulant medication and/or behavioral and psychosocial interventions depending on the patient’s age and comorbidities. Regarding stimulant medication, US treatment guidelines suggest the use of either methylphenidate- or amphetamine-containing products. Stimulants are available in long-acting and short-acting formulations, which offer several treatment options depending on patient’s age, adherence issues, social stigma, and abuse or misuse potential. Long-acting and short-acting formulations seem to be similarly efficacious and safe. However, short-acting formulations may be more suitable for younger children because they allow for adjustment to the optimal dose. Long-acting formulations offer a less frequent administration and may reduce stigma at school, increase adherence, and lower the risk of abuse and diversion.

Following a systematic literature search for head-to-head efficacy and safety comparisons among ADHD stimulants, 5 publications were identified. The majority of comparative evidence evaluated in this report comes from a drug class review from the Oregon DERP group, published in 2015. In addition, 2 SRs and 3 RCTs published after 2015 were included. Most identified evidence is limited and includes single, fair-quality, short-term head-to-head studies. Evidence mainly focused on children and adolescents (6 to 17 years of age). Comparative evidence in young children (< 6 years) and long-term comparative evidence in all age groups is not available. Overall, evidence from short-term RCTs suggests that no ADHD stimulant formulation is clearly superior to another regarding efficacy and safety in school-age children, adolescents, or adults with ADHD. Some RCTs did not find significant differences among ADHD stimulants and others showed inconsistent results depending on the ADHD rating scales utilized, dose comparisons, or time point of efficacy assessment (morning, afternoon, or evening). Among similarly efficacious preparations, there may be differences in the mode of delivery, pharmacokinetic profile (eg, duration of action), dosing, and adverse events.

In summary, current available comparative evidence on ADHD stimulants is insufficient to establish relevant efficacy and safety differences among these agents. Until more comparative evidence of higher quality is available, clinicians should individualize ADHD treatment based on patient´s age, coexisting conditions, symptom profile, abuse or diversion potential, social stigma, compliance, cost, and family or patient preferences. Conclusions drawn in the 2016 Utah Medicaid Pharmacy and Therapeutics (P&T) Committee regarding ADHD stimulants are supported by the new evidence found in the current report. For the purpose of the Utah Medicaid PDL, all ADHD stimulants may be considered equally safe and efficacious for the treatment of ADHD in children, adolescents, and adults. At least one long-acting and one short-acting formulation from each methylphenidate and amphetamine sub-category may be included as preferred. In addition, at least one formulation from each sub-category that is suitable for patients with difficulties to swallow a whole tablet or capsule (eg, younger children) may be considered as preferred (eg, oral solutions, oral suspensions, orally disintegrating tablets, or capsules that can be opened and mixed with food or drink).

45

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81. Chou WJ, Wang LJ, Lin CH, et al. Social adjustment and family function after drug switch from IR-methylphenidate to OROS-methylphenidate in patients with attention-deficit/hyperactivity disorder. Neuropsychiatr Dis Treat. 2018;14:2783-2791.

82. Newcorn JH, Nagy P, Childress AC, Frick G, Yan B, Pliszka S. Randomized, Double-Blind, Placebo-Controlled Acute Comparator Trials of Lisdexamfetamine and Extended-Release Methylphenidate in Adolescents With Attention-Deficit/Hyperactivity Disorder. CNS drugs. 2017;31(11):999-1014.

83. Kemper AR, Maslow GR, Hill S, Namdari B, Allen LaPointe NM, Goode AP, Coeytaux RR, Befus D, Kosinski AS, Bowen SE, McBroom AJ, Lallinger KR, Sanders GD. Attention Deficit Hyperactivity Disorder: Diagnosis and Treatment in Children and Adolescents. Comparative Effectiveness Review No. 203. (Prepared by the Duke University Evidence-based Practice Center under Contract No. 290-2015-00004-I.) AHRQ Publication No. 18-EHC005-EF. Rockville, MD: Agency for Healthcare Research and Quality; January 2018. Posted final reports are located on the Effective Health Care Program search page. DOI: https://doi.org/10.23970/AHRQEPCCER203.

84. Charach A, Dashti B, Carson P, et al. AHRQ Comparative Effectiveness Reviews. In: Attention Deficit Hyperactivity Disorder: Effectiveness of Treatment in At-Risk Preschoolers; Long-Term Effectiveness in All Ages; and Variability in Prevalence, Diagnosis, and Treatment. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011.

85. Bagot KS, Kaminer Y. Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. Addiction (Abingdon, England). 2014;109(4):547-557.

https://doi.org/10.23970/AHRQEPCCER203

50

86. Albertson TE. Chapter 8. Amphetamines. In: Olson KR, ed. Poisoning & Drug Overdose. 6th ed. New York, NY: McGraw-Hill; 2012.

87. Kaland ME, Klein-Schwartz W. Comparison of lisdexamfetamine and dextroamphetamine exposures reported to U.S. poison centers. Clinical toxicology (Philadelphia, Pa). 2015;53(5):477-485.

51

Appendix A: Literature Search Strategies for Systematic Reviews and Randomized Controlled Trials 1. Ovid Medline Literature Search Strategy

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to April

18, 2019

# Searches Results Notes

1 "attention deficit and disruptive behavior disorders"/ or attention deficit disorder with

hyperactivity/ or conduct disorder/ or child behavior disorders/ 48291

2 ("Attention deficit hyperactivity disorder" or ADHD or "AD/HD").ti,ab,kw,kf. 28620

3 ("Attention Deficit Disorder with Hyperactivity" or ADDH or ADD-H).ti,ab,kw,kf. 494

4 "Attention deficit disorder$".ti,ab,kw,kf. 2129

5 Hyperkinesis/ or ("Hyperkinetic disorder" or HKD).ti,ab,kw,kf. 4531

6 ((attention$ or behav$) adj3 (defic$ or dysfunc$ or disorder$)).ti,ab,kw,kf. 58651

7 ((Hyperkin$ or hyperactiv$) adj2 (defic$ or dysfunc$ or disorder$)).ti,ab,kw,kf. 25482

8 1 or 2 or 3 or 4 or 5 or 6 or 7 91899

9 Central Nervous System Stimulants/ 19142

10 ("Central Nervous System Stimulant$" or "CNS stimulant$" or stimulant$ or

psychostimulant$).ti,ab,kw,kf. 29599

11

Amphetamines/ or (Amphetamin$ or Amfetamin$).ti,ab,kw,kf. or

Dexmethylphenidate Hydrochloride/ or Dexmethylphenidat$.ti,ab,kw,kf. or

Dextroamphetamine/ or (Dextroamphetamin$ or Dextroamfetamin$).ti,ab,kw,kf. or

Lisdexamfetamine Dimesylate/ or (Lisdexamfetamin$ or

Lisdexamphetamine).ti,ab,kw,kf. or Methamphetamine/ or (Methamphetamin$.mp.

or Methamfetamin$).ti,ab,kw,kf. or Methylphenidate/ or Methylphenidat$.ti,ab,kw,kf.

47286

12 9 or 10 or 11 75781

13

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or

((systematic adj3 review$) or (systematic adj2 search$) or cochrane$ or (overview adj4

review)).ti,ab,kw,kf. or (cochrane$ or systematic review?).jw.

287607

McMASTER SR

and meta-

analysis specific

filter

14 (MEDLINE or systematic review).tw. or meta analysis.pt. 237724

15 13 or 14 318434

52

16

((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or

placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (exp animals/

not humans.sh.)

1112427

Cochrane Highly

Sensitive Search

Strategy Filter

17 8 and 12 and 16 2179

18 limit 17 to (english language and yr="2015 -Current") 418

19 limit 17 to (english language and yr="2017 -Current") 243 RCTs from 2017 to

April 18, 2019

20 8 and 12 and 15 486

21 limit 20 to (english language and yr="2015 -Current") 168

Systematic

reviews from

2015 to April 18,

2019 2. Embase Literature Search Strategy No. Query

Results 253

#27 #10 AND #20 AND #26 AND [2015-2019]/py

250,209 #26 (cochrane*:jt OR 'systematic review*':jt OR 'meta analysis'/mj OR 'systematic review'/mj OR ((systematic NEAR/3 review*):ti,ab,kw) OR ((systematic NEAR/2 search*):ti,ab,kw) OR 'meta analys*':ti,ab,kw OR metaanalys*:ti,ab,kw OR ((overview NEAR/4 (review OR reviews)):ti)) NOT ('conference abstract'/it OR 'conference review'/it) AND [english]/lim

270 #25 #10 AND #20 AND #24 NOT (#21 OR #22 OR #23) AND [2017-2019]/py

965,659 #24 ('clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'controlled study'/mj OR 'major clinical study'/mj OR 'randomized controlled trial'/mj OR 'control group'/mj OR (((clinical OR randomi* OR controlled OR multicentre OR multicenter OR 'multi centre' OR 'multi center' OR 'double-blind') NEAR/3 (study OR trial)):ti,ab) OR placebo:ab,ti OR 'head to head':ti,ab) AND [english]/lim

2,722,200 #23 animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti

53

OR livestock:ti OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de

6,735,494 #22 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de))

3,358,232 #21 'conference abstract'/it OR 'conference review'/it

632,354 #20 #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

456 #19 'amphetamine plus dexamphetamine'/exp OR 'mixed amphetamine salts':ti,ab,kw OR 'mixed amfetamine salts':ti,ab,kw

21,636 #18 'methylphenidate'/exp OR methylphenidat*:ti,ab,kw

20,061 #17 'methamphetamine'/exp OR methamphetamin*:ti,ab,kw OR methamfetamin*:ti,ab,kw

1,197 #16 'lisdexamfetamine'/exp OR lisdexamfetamin*:ti,ab,kw OR lisdexamphetamin*:ti,ab,kw

13,684 #15 'dexamphetamine'/exp OR dextroamphetamin*:ti,ab,kw OR dextroamfetamin*:ti,ab,kw OR dexamphetamin*:ti,ab,kw OR dexamfetamin*:ti,ab,kw

704 #14 'dexmethylphenidate'/exp OR dexmethylphenidat*:ti,ab,kw

51,470 #13 'amphetamine'/exp OR amphetamin* OR amfetamin*:ti,ab,kw

48,775 #12 'central nervous system stimulant*' OR 'central stimulant agent*' OR 'cns stimulant*' OR stimulant* OR psychostimulant*:ti,ab,kw

609,594 #11 'central stimulant agent'/exp OR 'psychostimulant agent'/exp

144,272

54

#10 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9

34,383 #9 ((hyperkin* OR hyperactiv*) NEAR/2 (defic* OR dysfunc* OR disorder* OR syndrom*)):ti,ab,kw

84,968 #8 ((attention OR behav*) NEAR/3 (defic* OR dysfunc* OR disorder* OR syndrom*)):ti,ab,kw

583 #7 'hyperkinetic disorder' OR hkd:ti,ab,kw

5,133 #6 'hyperkinesia'/exp

230 #5 addh OR 'add h':ti,ab,kw

39,778 #4 'attention deficit hyperactivity disorder':ti,ab,kw OR adhd:ti,ab,kw OR 'ad/hd':ti,ab,kw

61,927 #3 'hyperactivity'/de OR hyperactivit*:ti,ab,kw

6,863 #2 'conduct disorder'/exp

56,831 #1 'attention deficit disorder'/exp OR 'attention deficit disorder':ti,ab,kw 3. Epistemonikos Literature Search Strategy

(title:(ADHD OR "attention deficit" OR hyperactivity) OR abstract:(ADHD OR "attention deficit" OR hyperactivity)) AND (title:(stimulant* OR Amphetamine* OR amfetamine* OR dexmethylphenidate OR dextroamphetamine OR lisdexamfetamine OR methamphetamine OR methylphenidate) OR abstract:(stimulant* OR Amphetamine* OR amfetamine* OR dexmethylphenidate OR dextroamphetamine OR lisdexamfetamine OR methamphetamine OR methylphenidate))

55

Appendix B: Excluded References Table 1. List of Excluded References Wrong study design 1. Brown R, James A. Practical pharmacotherapy in child psychiatry: An update. BJ Psych Advances. 2015;

21(6):387-395 2. Buoli M, Serati M, Cahn W. Alternative pharmacological strategies for adult ADHD treatment: a systematic

review. Expert review of neurotherapeutics. 2016;16(2):131-14 3. Catala-Lopez F, Hutton B, Nunez-Beltran A, et al. The pharmacological and non-pharmacological treatment of

attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials. PloS one. 2017;12(7):e0180355.

4. Chan E, Fogler JM, Hammerness PG. Treatment of Attention-Deficit/Hyperactivity Disorder in Adolescents: A Systematic Review. JAMA. 2016;315(18):1997-2008.

5. Clavenna A, Bonati M. Pediatric pharmacoepidemiology - safety and effectiveness of medicines for ADHD. Expert opinion on drug safety. 2017;16(12):1335-1345.

6. Feldman ME, Charach A, Belanger SA. ADHD in children and youth: Part 2-Treatment. Paediatrics & child health. 2018;23(7):462-472.

7. Fridman M, Hodgkins PS, Kahle JS, Erder MH. Predicted effect size of lisdexamfetamine treatment of attention deficit/hyperactivity disorder (ADHD) in European adults: Estimates based on indirect analysis using a systematic review and meta-regression analysis. European psychiatry : the journal of the Association of European Psychiatrists. 2015;30(4):521-527.

8. Joseph A, Ayyagari R, Xie M, et al. Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison. European child & adolescent psychiatry. 2017;26(8):875-897.

9. Li Y, Gao J, He S, Zhang Y, Wang Q. An Evaluation on the Efficacy and Safety of Treatments for Attention Deficit Hyperactivity Disorder in Children and Adolescents: a Comparison of Multiple Treatments. Molecular neurobiology. 2017;54(9):6655-6669.

10. Padilha SCOS, Virtuoso S, Tonin FS, Borba HHL, Pontarolo R. Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis. European child & adolescent psychiatry. 2018;27(10):1335-1345.

11. Pelham WE, Smith BH, Evans SW, et al. The Effectiveness of Short- and Long-Acting Stimulant Medications for Adolescents With ADHD in a Naturalistic Secondary School Setting. Journal of attention disorders. 2017;21(1):40-45.

12. Pozzi M, Carnovale C, Peeters GGAM, et al. Adverse drug events related to mood and emotion in paediatric patients treated for ADHD: A meta-analysis. Journal of affective disorders. 2018;238(h3v, 7906073):161-178.

13. Rajeh A, Amanullah S, Shivakumar K, Cole J. Interventions in ADHD: A comparative review of stimulant medications and behavioral therapies. Asian journal of psychiatry. 2017;25(101517820):131-135.

14. Wigal T, Brams M, Frick G, Yan B, Madhoo M. A randomized, double-blind study of SHP465 mixed amphetamine salts extended-release in adults with ADHD using a simulated adult workplace design. Postgraduate medicine. 2018;130(5):481-493.

15. Zimovetz EA, Joseph A, Ayyagari R, Mauskopf JA. A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK. The European journal of health economics : HEPAC : health economics in prevention and care. 2018;19(1):21-35.

Wrong comparator 16. Castells X, Blanco-Silvente L, Cunill R. Amphetamines for attention deficit hyperactivity disorder (ADHD) in

adults. The Cochrane database of systematic reviews. 2018;8(100909747):CD007813. 17. Cerrillo-Urbina AJ, Garcia-Hermoso A, Pardo-Guijarro MJ, Sanchez-Lopez M, Santos-Gomez JL, Martinez-

Vizcaino V. The Effects of Long-Acting Stimulant and Nonstimulant Medications in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Meta-Analysis of Randomized Controlled Trials. Journal of child and adolescent psychopharmacology. 2018;28(8):494-507.

56

18. Chierrito de Oliveira D, Guerrero de Sousa P, Borges Dos Reis C, et al. Safety of Treatments for ADHD in Adults: Pairwise and Network Meta-Analyses. Journal of attention disorders. 2019;23(2):111-120

19. Cortese S, D'Acunto G, Konofal E, Masi G, Vitiello B. New Formulations of Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder: Pharmacokinetics, Efficacy, and Tolerability. CNS drugs. 2017;31(2):149-160.

20. De Crescenzo F, Cortese S, Adamo N, Janiri L. Pharmacological and non-pharmacological treatment of adults with ADHD: a meta-review. Evidence-based mental health. 2017;20(1):4-11.

21. Hennissen L, Bakker MJ, Banaschewski T, et al. Cardiovascular Effects of Stimulant and Non-Stimulant Medication for Children and Adolescents with ADHD: A Systematic Review and Meta-Analysis of Trials of Methylphenidate, Amphetamines and Atomoxetine. CNS drugs. 2017;31(3):199-215.

22. Punja S, Shamseer L, Hartling L, et al. Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews. 2016;2016(2).

23. Reading R. Stimulant medications and sleep for youth with ADHD: a meta-analysis. Child: Care, Health & Development. 2016;42(2):294-295.

Wrong outcome 24. Clarke AR, Barry RJ, Baker IE, McCarthy R, Selikowitz M. An Investigation of Stimulant Effects on the EEG of

Children With Attention-Deficit/Hyperactivity Disorder. Clinical EEG and neuroscience. 2017;48(4):235-242.

A more recent and robust systematic review is available 25. Coghill D, Banaschewski T, Zuddas A, Pelaz A, Gagliano A, Doepfner M. Erratum to: Long-acting

methylphenidate formulations in the treatment of attention-deficit/hyperactivity disorder: a systematic review of head-to-head studies. BMC psychiatry. 2015;15(100968559):202.

Only abstract available 26. Stuhec M, Lukic P, Locatelli I. Comparative efficacy of lisdexamfetamine, mixed amphetamine salts and

methylphenidate in treatment of attention deficit hyperactivity disorder in adults: A systematic review and meta-analysis. European Neuropsychopharmacology. 2016:S446.

Systematic Reviews reporting an absence of comparative evidence 27. Kemper AR, Maslow GR, Hill S, Namdari B, Allen LaPointe NM, Goode AP, Coeytaux RR, Befus D, Kosinski AS,

Bowen SE, McBroom AJ, Lallinger KR, Sanders GD. Attention Deficit Hyperactivity Disorder: Diagnosis and Treatment in Children and Adolescents. Comparative Effectiveness Review No. 203. (Prepared by the Duke University Evidence-based Practice Center under Contract No. 290-2015-00004-I.) AHRQ Publication No. 18-EHC005-EF. Rockville, MD: Agency for Healthcare Research and Quality; January 2018. Posted final reports are located on the Effective Health Care Program search page. DOI: https://doi.org/10.23970/AHRQEPCCER203.

https://doi.org/10.23970/AHRQEPCCER203

57

Appendix C: Direct Evidence from Systematic Reviews and Randomized Controlled Trials

Table 1. Systematic Reviews/Meta-Analyses of Central Nervous System Stimulant Agents Identified from 2015 to April 5, 2019 Reference/

Study Design Population Treatment Interventions Efficacy and Safety Results

Cortese, 201866 SR, MA, and NMA of RCTs (literature searches up to April 7, 2017)

Children, adolescents, or adults with ADHD

Amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate (including dexmethylphenidate), and modafinil, compared with each other or with placebo

Pairwise MA Head-to-head comparisons in children and adolescents: - Mean overall change in ADHD core symptoms (Clinician’s Ratings) at week 12:

o AMP vs. MPH (3 studies): SMD -0.32 (95% CI -0.47 to -0.16) [AMP showed a significantly better result compared to MPH]

- Functioning - Clinical Global Impression (CGI) at week 12: o AMP vs. MPH (4 studies): OR 1.74 (95% CI 1.19-2.55) [AMP showed a

significantly better result compared to MPH] - Tolerability (discontinuation due to adverse events)

o AMP vs. MPH [6 studies]: OR 1.78 (95% CI: 1.01-3.12) [tolerability was significantly better with MPH vs. AMP]

- Weight in Kg: o AMP vs. MPH (3 studies): SMD -0.25 (95% CI -0.50 to -0.01) [This result was

significantly better with MPH] - Systolic Blood Pressure

o AMP vs. MPH (3 studies): SMD 0.06 (95% CI -0.12-0.25) [This result favors MPH, although it is not statistically significant]

- Diastolic Blood Pressure o AMP vs. MPH (3 studies): SMD -0.01 (95% CI -0.14-0.11) [This result favors

AMP, although it is not statistically significant] - Acceptability:

o AMP vs. MPH (6 studies): OR 1.04 (95% CI 0.77; 1.41) [This result favors AMP, although it is not statistically significant]

- Data for AMP vs. MPH comparison was not available for the following endpoints in children and adolescents: mean overall change in ADHD core symptoms (teachers’ ratings), mean change in ADHD core symptoms (parents’ rating), and mean change in ADHD core symptoms (self-ratings). No data was available for AMP vs. MPH comparisons in adults

- Data was insufficient for the 26-week and 52-week time-points Luan, 201780

Children and adolescents (6 to

Lisdexamfetamine, Direct MA results in children and adolescents: MPH vs. LDX:

58

SR, pair-wise MA, and NMA of RCTs (literature searches up to March 2017)

18 years) with ADHD

atomoxetine, bupropion, clonidine, guanfacine, methylphenidate compared with each other or with placebo

Efficacy: - ADHD-RS: MD −5.80 (95% CI −8.93 to −2.67) [LDX showed significantly more

effectiveness than MPH] Safety: - All-cause withdrawal: OR 1.16 (95% CI 0.68-2.00) - Withdrawal due to adverse events: OR 0.4 (95% CI 0.08-2.13) - Withdrawal due to lack of efficacy: OR 2.00 (95% CI 0.93-4.35) - Abdominal pain: OR 0.67 (95% CI 0.18-2.44) (No significant differences regarding safety between MPH and LDX)

Kemper, 201883 AHRQ Report, 2018 (literature searches through November 7, 2016)

Children and adolescents with ADHD

Psychostimulants: MPH, DEX MPH, DEX AMP, LIS DEX, MAS, AMP, ATX, ER guanfacine, and others

Objective: To evaluate long-term efficacy and safety (≥ 6 months) among FDA-approved medications for ADHD (Strength of evidence = insufficient): - 2 head-to-head RCTs were identified; however, they did not compare ADHD stimulants

(1 RCT compared ATX with OROS MPH. The other RCT compared IR guanfacine, ER dexmethylphenidate, or the combination)

Conclusion: “The strength of evidence was insufficient to determine which drug is more effective or whether the side-effect profiles are different. There was also little evidence regarding serious cardiovascular risk with use of these medications”

McDonagh, 201579 Oregon DERP Report, 2015 (literature searches up to March-April 2015)

Children, adolescents, and adults with ADHD

Dextroamphetamine, dexmethylphenidate; lisdexamphetamine; methylphenidate ER ; methylphenidate immediate release; methylphenidate transdermal system

Young children (preschool age; 3-5 years): Comparative evidence not found Children (elementary school age; 6-12 years): 1. IR vs. SR formulations IR MPH vs. OROS MPH (Concerta): Comparative evidence was conflicting: - 2 double-blind trials showed no differences in ADHD symptom improvement - 2 open label studies showed better efficacy results with OROS MPH on some

assessments (not all) IR MPH vs. other ER formulations: Limited evidence: - 1 small RCT was unable to show differences between IR MPH and sustained release

MPH (Ritalin SR) - Non-inferiority of IR MPH vs. controlled-delivery MPH (Metadate CD) was

demonstrated in a 3-week study LIS DEX vs. OROS MPH: - 1 fair-quality RCT: More patients (18%) receiving LIS DEX achieved response (ie, a 30%

reduction in ADHD-RS score) and had more ADHD-RS score improvements at week 7 compared to OROS MPH. Better parent ratings were reported in the morning, afternoon, and evening with LIS-DEX vs. OROS MPH. No difference in the overall adverse event incidence. More discontinuations and cases of anorexia, decreased

59

appetite, decreased weight, insomnia, and nausea with LIS-DEX. More headaches and nasopharyngitis with OROS MPH

2. Sustained-release vs. sustained-release formulations MPH LA vs. OROS MPH - Limited evidence: 2 small cross-over studies showed superiority of MPH LA vs. OROS

MPH on some efficacy assessments (not all) MPH CD vs. OROS MPH - MPH CD was more efficacious than OROS MPH in the morning; similar in the

afternoon, and OROS MPH showed superiority in the evening - OROS MPH showed significantly higher rates of insomnia and decreased appetite vs.

MPH CD ER DEX MPH vs. OROS MPH - Limited evidence: 2 similar, fair-quality studies showed that ER DEX MPH had greater

response (ie, mean change in SKAMP combined scores) from 0.5 to 6 hours post dose vs. OROS MPH (primary endpoint). OROS MPH showed better results vs. ER DEX MPH from 10 to 12 hours post-dose

ER DEX MPH vs. XR MAS - Limited evidence (1 single, small, fair-quality RCT) showing no differences in efficacy

(response rate or symptom improvement) between groups after 8 weeks LIS DEX vs. XR MAS - No significant differences “using the SKAMP Deportment Scale (SKAMP-DS) scores in a

simulated classroom setting, or using the Clinical Global Impressions – Improvement (CGI-I) response rates after 1 week”

3. IR vs. IR formulations IR DEXAMP vs. IR MPH - Evidence (8 fair-quality RCTs) clearly shows no difference between groups - Short term trials and observational studies indicated that rates of weight loss are

higher with IR DEXAMP vs. IR MPH IR MAS vs IR MPH - 2 trials showed superiority of IR MAS vs. IR MPH regarding some efficacy assessments;

however, “clear evidence of superiority was lacking” DEX AMP vs. MAS - Limited evidence: IR DEX AMP was superior to DEX AMP SR in the morning. DEX AMP

SR was superior to MAS in the afternoon. - Transient weight loss was higher with MAS and DEX AMP SR vs. IR DEX AMP MPH TP vs. OROS MPH or IR MPH - 1 fair-quality trial: Similar efficacy between MPH TP and MPH OROS after 7 weeks

60

- 1 very small, fair-quality study: no significant differences between MPH TP and IR MPH after 12 hours in a simulated classroom. No significant differences in adverse events between MPH TP and IR MPH

Adolescents OROS MPH showed “better simulated driving scores (only in the late evening or nighttime)” vs. IR MPH and IR MAS Adults IR MPH vs. switching to OROS MPH Low-strength evidence (4 small short-term trials) showed similar efficacy on ADHD symptom improvement after 2 to 6 weeks. No differences in harms IR MAS vs. ER MAS Low-strength evidence (4 small short-term trials) showed similar efficacy on ADHD symptom improvement after 2 to 6 weeks. “Evidence was insufficient to draw conclusions on harms”

Charach, 201184 AHRQ Report, 2011 (literature searches through May 31, 2010)

Children, adolescents, and adults with ADHD

MPH, DEX, MAS, ATX, and ER guanfacine

Objective: To evaluate long-term efficacy and safety (≥ 6 months) among FDA-approved medications for ADHD (MPH, DEX, MAS, ATX, and ER guanfacine) Young children (< 6 years): Comparative evidence not found Children (≥ 6 years): Only observational safety studies comparing MPH vs. DEX, MPH vs. MAS, DEX vs. MPH, amphetamine vs. MPH, and MPH vs. DEX were found

Abbreviations: ADHD, attention deficit hyperactivity disorder; AHRQ, Agency for Healthcare Research and Quality; AMP, amphetamine; ATX, atomoxetine; CI, confidence interval; DERP, Drug Effectiveness Review Project; ER or XR, extended release, IR, immediate release; LA, long acting; LDX, lisdexamfetamine; MA, meta-analysis; MAS, mixed amphetamine salts; MD, mean deviation; MPH, methylphenidate; MTC, mixed treatment comparisons; NMA; network meta-analysis; OR, odds ratio; OROS, osmotic-release oral system; RCT, randomized controlled trial; SKAMP, Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale; SMD, standardized mean difference; SR, sustained release; SR, systematic review; TP, transdermal patch

61

Table 2. Head-To-Head Randomized Controlled Trials of Central Nervous System Stimulant Agents (Identified from 2017 to April 5, 2019) Reference/

Study Design Population Treatment Interventions Results Safety

Chou, 201881 Switching study (prospective, single-arm, open-label, 8-week, multicenter study)

Patients with ADHD (age 6 to 18 years)

Switching from IR MPH to OROS MPH

Results after switching from IR MPH to OROS MPH: - Changes in ADHD symptoms, as rated by parents or teachers using the

SNAP-IV scale: significant improvements with OROS MPH - Changes in patients’ social adjustment as assessed by SAICA after at least 4

weeks on OROS MPH o Significant improvements in school function (P < 0.001) o Significant improvements in peer relationships (P < 0.001) o Significant improvements in home behaviors (P < 0.001) o No significant improvements in the spare time function (P=0.828)

- ADHD symptom severity using CGI-S: o the severity of symptoms improved after switching

- Mental health status measured with a Chinese Health Questionnaire: o mental health status in mothers significantly improved at week 4 o mental health status in fathers did not significantly improved

Patients’ body weight: - Significant

reduction in weight at week 4 (0.8 kg, P=0.040) and week 8 (1.0 kg, P=0.006)

Newcorn, 201782

2 RCTs (one flexible-dose study and one forced-dose study)

Adolescents (13-17 years) with ADHD

Flexible-dose study Arms: once-daily LISDEX, OROS MPH, placebo (dosages could be titrated) Forced-dose study Arms: once-daily LISDEX 70 mg/day, OROS MPH 72 mg/day, placebo

Flexible-dose study Primary efficacy endpoint: The change in ADHD-RS-IV total score from baseline to end of study (week 8) - Least squares mean ± SEM change from baseline at end of study: no

significant differences between LISDEX and MPH OROS (p = 0.0717; ES -0.20)

- Improvements on ADHD severity using CGI-Severity (CGI-S) scale: no differences between groups (p = 0.6165)

Forced-dose study Primary efficacy endpoint: The change in ADHD-RS-IV total score from baseline to end of study (week 6): - Least squares mean ± SEM change from baseline at end of study

statistically favored LISDEX vs. MPH OROS (p = 0.0013; ES -0.33) - Improvements at end of study on ADHD severity using CGI-Severity (CGI-S)

scale: LISDEX > OROS MPH (p=0.0188)

Safety profile of LISDEX and OROS MPH was consistent with previous reports

Abbreviations: ADHD, attention deficit hyperactivity disorder; ADHD-RS, ADHD rating scale; CGI, Clinical Global Impression; ES, effect size; MPH, methylphenidate hydrochloride; SAICA, Social Adjustment Inventory for Children and Adolescents; SEM, standard error of the mean; SNAP-IV, Swanson, Nolan, and Pelham version IV

utah medicaid pharmacy and therapeutics committee drug ... · approved by the u.s. food and drug...

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